Bridged carbapenem antibacterial compounds

ABSTRACT

Carbapenems of the formula ##STR1## are useful antibacterial agents.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass in which the five membered ring of the carbapenem nucleus is fusedto a multi-ring group which is substituted by various cationic andneutral substituents. The fused ring compounds are described in detailbelow.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

U.S. Pat. Nos. 5,011,832 and 5,025,006 relate to carbapenems of thestructure shown below which exhibit antimicrobial activity againststrains of methicillin resistant staphylococci (MRSA). The carbapenemsdescribed therein possess a meta-disposed biphenyl moiety attached tothe C-2 position of the carbapenem ring. ##STR4##

U.S. Pat. Nos. 4,374,849 and 4,374,879 issued on Feb. 22, 1983 toChristensen, et al. relate to compounds of the formula: ##STR5##

In U.S. Pat. No. 4,374,878, the R group noted above represents a hydroxysubstituted ethyl group.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR6##

Compounds of the formula: ##STR7## have been disclosed in EPO 422,596 A3published on Apr. 17, 1991.

European Publication No. 416 953 A3 published on Mar. 13, 1991 addressescompounds of the formula: ##STR8##

European Publication No. 517 065 A1 published on Dec. 9, 1992 addressescompounds of the formula: ##STR9##

The carbapenems of the present invention are effective against grampositive microorganisms, especially methicillin resistant Staphylococcusaureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE),and methicillin resistant coagulase negative Staphylococci (MRCNS). Theantibacterial compounds of the present invention thus comprise animportant contribution to therapy of these difficult to controlpathogens.

Moreover, there is an increasing need for agents effective against suchpathogens (MRSA/MRCNS) which are at the same time safe, i.e., relativelyfree from undesirable side effects. And, the current agent of choice,vancomycin, a glycopeptide antibacterial, is experiencing an everincreasing amount of resistance in the MRSA/MRCNS pathogens.

SUMMARY OF THE INVENTION

The present invention addresses a compound represented by formula I:##STR10## wherein: m is an integer 0, 1, 2, 3, 4 or 5;

n is an integer 0, 1, 2, 3 or 4;

X represents (a) a bond; (b) --O--; (c) --S(O)_(x) -- with x equal to 0,1 or 2; (d) --C(O)--; (e) --NR'-- with R' representing H, C₁ to C₄alkyl, acetyl or C₁₋₄ alkyl substituted with R^(q) ; (f) --CH═CH--; (g)--C(O)NR'--; (h) --NR'C(O)--; (i) --CO₂ -- (j) --OC(O)--; (k) --SO₂NR'-- or (l) --NR'SO₂ --.

The values of m, n and X are selected such that ring B constitutes a 6to 10 membered ring.

Y represents H, a negative charge, a pharmaceutically acceptable ester,a biolabile ester, a carboxylate protecting group or a metal cation.

R¹ and R² independently represent H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--,HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ -- or (CH₃)₂ CF--.

One of Z and Z' represents a bond and the other represents one of:--CH═CH--, --C(O)NR^(f) --, --NR^(f) C(O)--, --S(O)_(x) NR^(f) --,--NR^(f) S(O)_(x) --, --C(O)--, --OC(O)--, --C(O)O--, --O--, --S(O)_(x)--, with x=0, 1 or 2, or --NR^(f) --, with R^(f) representing H, C₁₋₄alkyl, --C(O)--C₁₋₄ alkyl, --C(O)C₁₋₄ alkyl substituted with R^(q), suchthat ring C is a 5 or 6 membered ring.

One of the R^(a) groups represents H or W, and the other represents oneof the groups (a) through (d): ##STR11##

When one of the R^(a) groups represents (a) ##STR12## A represents--(CR³ R⁴)_(r) --Q--(CR³ R⁴)s-- wherein r is 0-6, s is 1-6 and Qrepresents: a covalent bond --O--, --S(O)_(x) -- with x equal to 0, 1 or2, --NR³ --, --SO₂ NR³ --, --NR³ SO₂ --, --C(O)NR³ --, --NR³ C(O)--,--CR³ ═CR⁴ --, --C(O)--, --OC(O)-- or --(O)CO--; with R³ and R⁴independently representing H or C₁₋₄ lower alkyl, and (CR³ R⁴)_(s) --being attached to the ring nitrogen. ##STR13## represents a 5 or 6membered monocyclic heterocycle or an 8-10 membered bicyclicheterocycle, bonded to A through the ring nitrogen and having asubstituent group R^(d) optionally attached to the ring nitrogen, andhaving 0-3 R^(c) groups attached to other atoms of the heterocyclicgroup, said ring nitrogen being tertiary or quaternary by virtue of A,the ring bonds and optionally R^(d) which may be attached, saidheterocyclic group being aromatic, partially aromatic or non-aromatic.

The heterocycle also contain 0-3 additional nitrogen atoms and 0-1oxygen or sulfur atom.

Each R^(c) independently represents W as defined below or NR^(y) R^(z),wherein R^(y) and R^(z) independently represent H, C₁ to C₄ alkyl or C₁to C₄ alkyl substituted with R^(q), or R^(y) and R^(z) are takentogether to represent either a 3- to 5-membered alkylidene radical toform a ring, optionally substituted with Rq, or a 2- to 4-memberedalkylidene radical interrupted by O or S(O)_(x) with x equal to 0, 1 or2, to form a ring, said alkylidene being optionally substituted withR^(q).

R^(q) is selected from hydroxy, methoxy, cyano, --C(O)NH₂, --OC(O)NH₂,--CHO, --OC(O)N(CH₃)₂, --SO₂ NH₂. --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃,--F, --CF₃, --SO₃ M^(b) with M^(b) representing H or alkali metal, or--CO₂ M^(a), where M^(a) is H, alkali metal, methyl or phenyl;tetrazolyl (where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byM^(a) as defined above).

Each R^(d) independently represents hydrogen, NH₂, O-- or C₁ to C₄alkyl, optionally monosubstituted with R^(q) as defined above.

When one R^(a) group represents .sup.(b) ##STR14## A' represents --(CR³R⁴)_(m') --Q--(CR³ R⁴)_(m') -- with each m' independently equal to 0-6,and Q, R³ and R⁴ as defined above, except that when each m' is 0, Q isnot a covalent bond, and --(CR³ R⁴)_(m') attached to the phenyl ring.##STR15## represents a 5 or 6 membered monocyclic heterocycle or an 8-10membered bicyclic heterocycle, said heterocycle being aromatic,partially aromatic or non-aromatic, bonded to A' through an atom otherthan the ring nitrogen, and optionally having 0-2 R^(d) substituentgroups attached to the ring nitrogen, said nitrogen in the heterocyclebeing tertiary or quaternary by virtue of the ring bonds and theoptional R^(d) groups which may be attached.

The heterocycle may further contain 0-1 oxygen or sulfur atom and 0-2additional nitrogen atoms therein.

R^(c) and R^(d) are as defined above.

When one R^(a) group represents (c) --A_(p) --NR¹⁰ R¹¹ R¹² (0-1),

A is as defined above and p is an integer 0 or 1.

R¹⁰, R¹¹ and when present, R¹², are independently H, C₁₋₄ alkyl or C₁₋₄alkyl monosubstituted with R^(q) ; or R¹⁰, R¹¹ and R¹² may be taken incombination to represent a C₄ to C₁₀ alkanetriyl group, optionallysubstituted with up to three W groups, with W as defined below.

Where one R^(a) group represents (d), A', p, the N containing ring,R^(c) and R^(d) are as previously defined.

When present, each W independently represents a member selected from thegroup consisting of:

a) trifluoromethyl group which is --CF₃ ;

b) a halogen atom selected from the group consisting of: --Br, --Cl,--F, or --I;

c) C₁ -C₄ alkoxy radical which is --OC₁₋₄ alkyl, wherein the alkyl isoptionally mono-substituted by R^(q), where R^(q) is as defined above;

d) a hydroxy group which is --OH;

e) a carbonyloxy radical which is --OC(O)R^(s), where R^(s) is C₁₋₄alkyl or phenyl, each of which is optionally mono-substituted by R^(q)as defined above;

f) a carbamoyloxy radical which is --OC(O)N(R^(y))R^(z), where R^(y) andR^(z) are independently H, C₁₋₄ alkyl, (optionally mono-substituted byR^(q) as defined above), or are taken together to represent a 3- to5-membered alkylidene radical which forms a ring (optionally substitutedwith R^(q) as defined above), or a 2- to 4-membered alkylidene radicalinterrupted by --O--, --S--, --S(O)-- or --S(O)₂ -- which forms a ring,said ring being optionally mono-substituted with R^(q) as defined above;

g) a sulfur radical which is --S(O)_(n) --R^(s), where n=0-2, and R^(s)is defined above;

h) a sulfamoyl group which is --SO₂ N(R^(y))R^(z), where R^(y) and R^(z)are as defined above;

i) azido which is N₃

j) a formamido group which is --N(R^(t))C(O)H, where R^(t) is H or C₁₋₄alkyl, said alkyl group being optionally mono-substituted with R^(q) asdefined above;

k) an alkylcarbonylamino radical which is --N(R^(t))C(O)C₁₋₄ alkyl,wherein R^(t) is as defined above;

l) an alkoxycarbonylamino radical which is --N(R^(t))C(O)OC₁₋₄ alkyl,where R^(t) is as defined above;

m) a ureido group which is --N(R^(t))C(O)N(R^(y))R^(z) where R^(t),R^(y) and R^(z) are defined above;

n) a sulfonamido group which is --N(R^(t))SO₂ R^(s), where R^(s) andR^(t) are as defined above;

o) a cyano group which is --CN;

p) a formyl or acetalized formyl radical selected from the groupconsisting of --C(O)H and --CH(OCH₃)₂ ;

q) an alkylcarbonyl radical wherein the carbonyl is acetalized:--C(OCH₃)₂ C₁₋₄ alkyl, where the alkyl is optionally mono-substituted byR^(q) as defined above;

r) a carbonyl radical which is --C(O)R^(s), where R^(s) is as definedabove;

s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group which is--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring;

t) an alkoxycarbonyl radical which is --C(O)OC₁₋₄ alkyl, where the alkylis optionally mono-substituted by R^(q) as defined above;

u) a carbamoyl radical which is --C(O)N(R^(y))R^(z), where R^(y) andR^(z) are as defined above;

v) an N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in whichthe nitrogen atom may be additionally substituted by a C₁ -C₄ alkylgroup which is --C(O)N(OR^(y))R^(z), where R^(y) and R^(z) are asdefined above, except they may not be joined together to form a ring;

w) a thiocarbamoyl group which is --C(S)N(R^(y))R^(z) where R^(y) andR^(z) are as defined above;

x) carboxyl which is --COOM^(a) where M^(a) is as defined above;

y) thiocyanate which is --SCN;

z) trifluoromethylthio which is --SCF₃ ;

aa) tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above;

ab) an anionic function selected from the group consisting of phosphono[P═O(OM^(a))₂ ]; alkylphosphono {P═O(OM^(a))-[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OM^(a))-(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(a))N(R^(y))R^(z) and P═O(OM^(a))NHR^(x) ]; sulfino (SO₂ M^(a));sulfo (SO₃ M^(a)); acylsulfonamides selected from the structures SO₂NM^(a) CON(R^(y))R^(z) ; and SO₂ NM^(a) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms, in which a carbon atom isthe point of attachment, in which one of the carbon atoms has beenreplaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), said R^(q), M^(a), R^(y) and R^(z) being asdefined above;

ac) a C₅ -C₇ cycloalkyl group in which one of the carbon atoms in thering is replaced by a heteroatom selected from O, S, NH, or N(C₁ -C₄alkyl) and in which one additional carbon may be replaced by the NH orN(C₁ -C₄ alkyl), and in which at least one carbon atom adjacent to eachnitrogen heteroatom has both of its attached hydrogen atoms replaced byone oxygen thus forming a carbonyl moiety and there are one or twocarbonyl moieties present in the ring;

ad) a C₂ -C₄ alkenyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above and phenyl which is optionally substitutedby R^(q) as defined above;

ae) a C₂ -C₄ alkynyl radical, optionally mono-substituted by one of thesubstituents a) to ac) above;

af) a C₁ -C₄ alkyl radical;

ag) a C₁ -C₄ alkyl group mono-substituted by one of the substituentsa)-ac) above;

ah) a 2-oxazolidinonyl moiety in which the point of attachment is thenitrogen atom of the oxazolidinone ring, the ring oxygen atom isoptionally replaced by a heteroatom selected from S and NR^(t) (whereR^(t) is as defined above) and one of the saturated carbon atoms of theoxazolidinone ring is optionally mono-substituted by one of thesubstituents a) to ag) above.

Novel compositions, intermediates, processes of manufacture and methodsof treatment are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 10 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl andcyclohexyl. When substituted, alkyl groups may be substituted with up tofour substituent groups, W, as defined, at any available point ofattachment. When the alkyl group is said to be substituted with an alkylgroup, this is used interchangeably with "branched alkyl group".

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings which are fused

The term "alkenyl" refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferred alkenyl groups include etenyl, propenyl,butenyl and cyclohexenyl.

The term "alkynyl" refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Preferred alkynyl groups include ethynyl, propynyland butynyl.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and thelike, groups as well as rings which are fused, e.g., naphthyl,phenanthrenyl and the like. Aryl thus contain at least one ring havingat least 6 atoms, with up to five such rings being present, containingup to 22 atoms therein, with alternating (resonating) double bondsbetween adjacent carbon atoms or suitable heteroatoms. The preferredaryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups maylikewise be substituted with R^(a) and W groups as defined below.Preferred substituted aryls include phenyl and naphthyl substituted withone or two preferred R^(a) or W groups.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon grouphaving 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10atoms, containing at least one heteroatom, O, S or N, in which a carbonor nitrogen atom is the point of attachment, and in which one additionalcarbon atom is optionally replaced by a heteroatom selected from O or S,and in which from 1 to 3 additional carbon atoms are optionally replacedby nitrogen heteroatoms, said heteroaryl group being optionallysubstituted with up to four R^(q) groups.

Heteroaryl thus includes aromatic and partially aromatic groups whichcontain one or more heteroatoms. Examples of this type are pyrrole,pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms maybe present together with the first nitrogen and oxygen or sulfur,giving, e.g., thiadiazole. The preferred heteroaryls are those whereonly nitrogen heteroatoms are present when there is more than one.Typical of these are pyrazole, tetrazole, imidazole, pyridine,pyrimidine and pyrazine and triazine.

The heteroaryl group of R^(x) may be optionally substituted by R^(q), asdefined above, and substitution can be on one of the carbon atoms or oneof the heteroatoms, although in the latter case certain substitutentchoices may not be appropriate.

The term "heterocycloalkyl" refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S, NH, or N(C₁ -C₄ alkyl), and in which up to threeadditional carbon atoms may be replaced by said hereto groups.

The term "quaternary nitrogen" refers to a tetravalent positivelycharged nitrogen atom including, e.g., the positively charged nitrogenin a tetraalkylammonium group (e.g. tetramethylammonium,N-methylpyridinium), the positively charged nitrogen in a protonatedammonium species (e.g. trimethylhydroammonium, N-hydropyridinium), thepositively charged nitrogen in an amine N-oxide (e.g.N-methylmorpholine-N-oxide, pyridine-N-oxide), and the positivelycharged nitrogen in an N-amino-ammonium group (e.g. N-aminopyridinium).

The term "heteroatom" means N, S, or O, selected on an independentbasis.

Alkylene (alkylidene or alkanediyl) and arylene refer to the groupsnoted above with divalent points of attachment. For example, phenyleneis an arylene group, attached at any of the 1, 2- 1, 3- or 1,4-positions. Examples of alkylene include --CH₂ --, --CH₂ CH₂ --, --CH₂CH₂ CH₂ --, ##STR16##

Similarly, alkanetriyl refers to an alkane-derived group with threepoints of attachment. Alkanetriyl groups contain from five to fifteencarbon atoms, which may be straight, branched, cyclic or multicyclic.

Aralkyl is a specie of substituted alkyl, containing up to three arylgroups substituted on a straight, branched or cycloalkyl group. The mostpreferred aralkyl group is benzyl.

Halogen, or "halo" refers to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C₁ -C₄ alkyl--O--, with the alkyl group optionallysubstituted with the variable R^(q).

Carbonyloxy refers to the radical: --OC(O)R^(s), where R^(s) is C₁₋₄alkyl or phenyl, each of which is optionally mono substituted by R^(q).

Carbamoyloxy refers to the radical: --OC(O)N(R^(y))R^(z), where R^(y)and R^(z) are independently H, C₁₋₄ alkyl, (optionally mono-substitutedby R^(q) as defined above). Alternatively, R^(y) and R^(z) can be takentogether to represent a 3- to 5-membered alkylidene radical which formsa ring (optionally substituted with R^(q) as defined above), or a 2- to4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- or--S(O)₂ -- which forms a ring, said ring being optionallymono-substituted with R^(q) as defined above.

The term "sulfur radical" refers to the group: --S(O)_(x) --R^(s), wherex is an integer of from O to 2, and R^(s) is as defined above.

The term "sulfamoyl group" refers to: "SO₂ N(R^(y))R^(z), where R^(y)and R^(z) are as defined above, representing H, alkyl or alkylmonosubstituted with R^(q).

The term "azido" refers to the group: N₃.

The term "formamido" refers to the group: --N(R^(t))C(O)H, where R^(t)is H or C₁₋₄ alkyl, said alkyl group being optionally mono-substitutedwith R^(q) as defined above.

The term "alkylcarbonylamino" refers to the group: --N(R^(t))C(O)C₁₋₄alkyl, wherein R^(t) is as defined above.

The term "alkoxycarbonylamino" refers to the group:

--N(R^(t))C(O)OC₁₋₄ alkyl, where R^(t) is as defined above.

The term "ureido" refers to the group: --N(R^(t))C(O)N(R^(y))R^(z) whereR^(t), R^(y) and R^(z) are defined above.

The term "sulfonamido" refers to the group: --N(R^(t))SO₂ R^(s), whereR^(s) and R^(t) are as defined above.

The terms "formyl" and "acetalized formyl radical" refer to the groups:--C(O)H or --CH(OCH₃)₂, respectively. Thus, an alkylcarbonyl radicalwherein the carbonyl is acetalized is of the formula: --C(OCH₃)₂ C₁ -C₄alkyl, where the alkyl is optionally mono-substituted by R^(q).

A "carbonyl radical" is represented by the formula: --C(O)R^(s), whereR^(s) is as defined above.

A "hydroximinomethyl" radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group is represented by theformula: --(C═NOR^(z))R⁴ where R^(y) and R^(z) are as defined above,except they may not be joined together to form a ring.

An "alkoxycarbonyl" radical is represented by the formula: --C(O)OC₁₋₄alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above.

A "carbamoyl" radical is represented by the formula:--C(O)N(R^(y))R^(z), where R^(y) and R^(z) are as defined.

An N-hydroxycarbamoyl or N(C₁ -C₄ alkoxy)carbamoyl radical in which thenitrogen atom may be additionally substituted by a C₁ -C₄ alkyl group isrepresented by the formula: --C(O)N(OR^(y))R^(z), where R^(y) and R^(z)are as defined above, except they may not be joined together to form aring.

A "thiocarbamoyl group" is represented by the structural formula:--C(S)N(R^(y))R^(z) where R^(y) and R^(z) are as defined above.

A "carboxyl group" is represented by the structural formula: --COOM^(a)where M^(a) is as defined above.

The term "tetrazolyl" is a heteroaryl group where the point ofattachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is optionally mono-substituted by an alkali metal or a C₁-C₄ alkyl optionally substituted by R^(q).

The term "anionic function" refers to the members of the group:phosphono [P═O(OM^(a))₂ ]; alkylphosphono {P═O(OM^(a))-[O(C₁ -C₄alkyl)]}; alkylphosphinyl [P═O(OM^(a))-(C₁ -C₄ alkyl)]; phosphoramido[P═O(OM^(a))N(R^(y))R^(z) and P═O(OM^(a))NHR^(x) ]; sulfino (SO₂ M^(a));sulfo (SO₃ M^(a)); acylsulfonamides selected from: SO₂ NM^(a)CON(R^(y))R^(z) ; and SO₂ NM^(a) CN, where R^(x) is phenyl orheteroaryl.

The carbapenems of the present invention contain a ring which has beendesignated "B". Ring B is fused between the carbapenem 5 membered ringand a phenyl ring. Ring B may be from 6 to 10 membered, optionallycontaining a heteroatom, such as when X represents NR', O or S(O)_(x)with x equal to an integer, 0, 1 or 2. When X represents NR', thevariable group R' may be hydrogen, acetyl, acetyl substituted with Rq,or C₁ to C₄ alkyl, optionally substituted with R^(q).

Ring B is also formed by the alkylene groups, (CH₂)_(m) and (CH₂)_(n)which may be present. In certain instances, not all values of m and nare included in combination. When X represents a direct bond, the sum ofm and n is between 2 and 6. When X represents any of the groups otherthan a bond, the sum of m and n is from 0 to 5. Thus, ring B constitutesa 6 to 10 membered ring.

Preferred values of m and n are such that ring B is six membered, with Xpreferably representing a direct bond or a heteroatom, O, S or NH.

Ring C is a 5 or 6 membered ring fused between the two phenyl rings. Oneof Z and Z' represents a bond, and the other variable represents avinylene (--CH═CH--) bridge, a carbonyl group, an ester, reverse ester,a heteroatom, e.g., an ether or thioether; sulfoxide, sulfone, or anamine. Also, one of Z and Z' may represent --C(O)NR^(f) --, --NRC(O)--,--S(O)_(x) NR^(f) -- or --NR^(f) S(O)_(x) -- wherein x represents 0, 1or 2. R^(f) represents H, C₁₋₄ alkyl, --C(O)C₁₋₄ alkyl, --C(O)C₁₋₄ alkylsubstituted with R^(q), --NR^(t) C(O)C₁₋₄ alkyl or --NR^(t) C(O)C₁₋₄alkyl substituted with R^(q).

Variables R³ and R⁴ independently represent H or lower alkyl.

One of the R^(a) groups represents a nitrogen containing group, (a)through (d) as described above. The other R^(a) variables represent anuncharged specie selected from H, the variables for W and NR^(y) R^(z).

The values of R^(a) (a) through (d) shown above can be charged oruncharged. For clarity, the positive charge has not been drawn in groups(a) through (d). When the particular nitrogen containing group is drawnas having four points of attachment, such as by attachment to the Amoiety, ring bonds, R^(d) group or groups or R¹⁰, R¹¹ and R¹², thenitrogen is considered quaternary and positively charged. When thenitrogen drawn in any of groups (a) through (d) has only three points ofattachment, the nitrogen is tertiary and uncharged. Tertiary nitrogencontaining groups can be quaternized by standard procedures, such as theMenshutkin reaction. Both charged and uncharged nitrogen-containingcompounds are included in the invention.

When one of the R^(a) variables represents group (a), the spacer moiety--A-- forms an alkylene chain, optionally interrupted with a heteroatomor functional group, --Q--. The length of A ranges from a methylenegroup to an alkyl chain of 12 carbon atoms in length, optionally alsocontaining --Q-- noted above. The --A-- moiety bonds to the nitrogencontaining ring through the N shown, and to the phenyl ring shown.

The heterocyclic group to which --A-- bonds may be a heteroaryl group, apartially aromatic heterocycle or a non-aromatic heterocycle, with asubstituent R^(d) optionally bonded to the ring nitrogen. When theheterocycle is aromatic, the ring nitrogen is either uncharged orpositively charged by virtue of the attachment to --A--, the ring bondsand R^(d). R^(d) would not be required to quaternize said ring nitrogenin (a) when the ring is aromatic. Thus, the aromatic, partially aromaticand non-aromatic forms may contain neutral or positively charge nitrogenatoms.

When the ring nitrogen atom is uncharged, the substituent group R^(d) isnot present on the ring nitrogen.

The heterocyclic group may also optionally contain up to threeadditional nitrogen atoms and up to one oxygen or sulfur atom. Theheterocycle can also be substituted with up to three R^(c) groups at anyavailable points of attachment, either via carbon or nitrogen atoms.

When one of the R^(a) variables represents group (b), the spacer moietyis --A'-- which represents an alkylene group, optionally interruptedwith a heteroatom, Q. The ring structure is bonded to --A'-- through anatom other than a ring nitrogen. The heterocycle can be aromatic,partially aromatic or non-aromatic. Like (a), the ring nitrogen may bepositively charged or uncharged. The ring nitrogen is optionallysubstituted with one or two groups R^(d), as desired. When two R^(d)groups are present on the ring nitrogen which is shown, and thestructure is non-aromatic, the nitrogen is positively charged. Also,when the ring is aromatic and one R^(d) is present on the ring nitrogen,the nitrogen is positively charged. When the ring is non-aromatic andthere is one R^(d) group present, the nitrogen is uncharged. Hence, thenitrogen may have up to two R^(d) groups present thereon, depending onthe particular configuration desired.

Also, up to three R^(c) groups may be substituted onto the ring, at anyavailable point of attachment.

When the variables and substituent groups are shown with bonds attached,e.g., --A--, --R^(c), etc., this is to serve as a point of reference forapplication to the generic structure, and does not indicate that doubleor triple bonds are intended.

When one of the R^(a) variables represents group (c), The spacer moiety--A-- represents an optional alkylene group, which in turn is optionallyinterrupted with Q, which may be a heteroatom, substituted amine,sulfonamide and the like, as described above with respect to group (a).The nitrogen bound to the --A-- spacer moiety is either uncharged, suchas when R¹² is absent, or quaternary by virtue of the R¹⁰, R¹¹ and R¹²groups present thereon and --A-- attached thereto. These R groups mayindependently represent H, alkyl or substituted alkyl groups.

Alternatively, R¹⁰, R¹¹ and R¹² may be taken together to represent a C₄to C₁₀ alkanetriyl group, bonded to the nitrogen. Thus, the nitrogen isquaternary.

When one of the R^(a) variables represents group (d), --A'-- is asdefined above for group (b). The thioether bridge is attached to theheterocyclic moiety through an atom in the ring other than the nitrogenatom which is shown.

The variable p is either 0 or 1, making the --A'-- spacer moietyoptional. There is a thioether bridge between the --A'-- spacer moietywhen present, and the heterocyclic group, or between the phenyl ring towhich (d) is attached and the heterocyclic ring which is part of (d).

As noted above with respect to group (b), the nitrogen may be part of anaromatic ring, a partially aromatic heterocycle or a non-aromaticheterocycle and may be unsubstituted, or substituted. The nitrogen maybe quaternary with one or two R^(d) groups as desired.

In each instance above, one of the R^(a) variables represents a groupselected from (a) through (d) and the other R^(a) group represents H,NR^(y) R^(z) or one of the values of W.

The bond at position one is shown as a wavy line in many instances. Thisindicates that the configuration of the carbon atom at position one isalpha or beta, or the compound is a mixture of isomers. The preferredconfiguration is beta.

In the compounds of the present invention, the R^(a) substituent maycontribute to the anti-MSRA/MRCNS activity of the overall molecule, orto the other properties of the molecule.

Some R^(a) substituents may be distinguishable from others chemically orwith respect to the biological properties which they confer. In relatedcompounds, it has been found that the charged compounds may affordgreater water solubility and reduced potential for CNS side effects.Substituents which tend to confer improved water solubility on theoverall compound have been found useful, since they are contemplated toimprove the pharmacokinetics of the compound involved. Although asubstantial number and range of R^(a) substituents has been describedherein, all of these are contemplated to be a part of the presentinvention in connection with the genus of formula I.

When a group is termed "substituted", unless otherwise indicated, thismeans that the group contains from 1 to 3 substituents R^(q) thereon.With respect to alkyl groups, the substituents thereon are selected fromthe variables specified for W. Preferred substituent groups include C₁₋₄alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, hydroxy, C₁₋₄ alkoxy, aryl,heteroaryl, aralkyl, halo, cyano, nitro, carboxyl and the anionicfunction groups, as these terms are defined above.

When a functional group is termed "protected", this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as McOmie, J. (ed) Protecting Groups in OrganicChemistry pp. 46-119 (1973).

The preferred compounds of the invention include compounds wherein R¹and R² include H and substituted lower alkyl, respectively. Preferredsubstituent groups include F and hydroxy. Particularly preferred arecompounds where one of R¹ and R² is H, and the other is 1-hydroxyethyl.In the most preferred compounds R¹ represents H, and R² represents (R)CH₃ CH(OH)--. The designation (R) defines the absolute configuration ofthe stereocenter.

The preferred compounds of the invention also include compounds wherethe uncharged R^(a) variable represents H, halo, alkylthio,alkylsulfonyl or cyano.

The preferred compounds also include compounds where ring B has 6 or 7atoms.

One preferred subgenus included in the invention relates to compoundsrepresented by structural formula Ia: ##STR17## wherein one Rarepresents a group (a) through (d) and the other Ra represents W; Wrepresents any of the groups recited above; Y represents H, a biolabileester, a pharmaceutically acceptable cation or a negative charge, and Zrepresents --C(O)--, --O-- or --S(O)_(x) with x equal to zero.

Another preferred subgenus included in the invention relates tocompounds represented by structural formula Ib: ##STR18## wherein thevalues of Z, Y, R^(a) and W are as described above with respect toformula Ia.

Another preferred subgenus included in the invention relates tocompounds represented by structural formula Ic: ##STR19## wherein thevalues of Y, R^(a) and W are as described above with respect to formulaIa, and Z represents any of the values recited for Z in formula Ia.

Another subgenus included in the invention relates to compoundsrepresented by structural formula Id: ##STR20## wherein the values of Z,Y, R^(a) and W are as described above with respect to formula Ia.

Another subgenus included in the invention relates to compoundsrepresented by structural formula Ie: ##STR21## wherein the values of Z,Y, R^(a) and W are as described above with respect to formula Ia.

Another subgenus included in the invention relates to compoundsrepresented by structural formula If: ##STR22## wherein the values of Z,Y, R^(a) and W are as described above with respect to formula Ia.

Another subgenus included in the invention relates to compoundsrepresented by structural formula Ig: ##STR23## wherein the values of Z,Y, R^(a) and W are as described above with respect to formula Ia.

Another subgenus included in the invention relates to compoundsrepresented by structural formula Ih: ##STR24## wherein the values of Z,Y, R^(a) and W are as described above with respect to formula Ia.

Preferred values of R^(a) type (a) include the following structures:##STR25## where X'=O, S, or N. Other preferred values of (a) include thestructures shown above in non-aromatic form with R^(d) present orabsent, and the ring nitrogen in uncharged form.

Where R^(c) groups are shown to have an indefinite position, they areattached to any available site of the ring. Also, in fused heterocycles,where more than one R^(c) group is shown, this means that substitutionwith up to three R^(c) can be present. Hence, when R^(c) appears twicein a two ring structure, there can be up to three such R^(c) groups inthe rings.

Preferred values of R^(a) type (b) include: ##STR26## where X'=O or S.Other preferred values of (b) include the structures shown above inuncharged form. In each such instance, the group or groups R^(d) areabsent.

For structures of type (b), where R^(c) and/or A' are shown to haveindefinite positions, they are independently attached to any availableatom of the ring.

Preferred R^(a) type (c) substituents include: ##STR27##

Preferred R^(a) type (d) values include: ##STR28## Other preferredvalues of (d) include the structures shown above in uncharged form. Inthese structures, the R^(d) may be monosubstituted on or the nitrogenatom or absent.

The compounds of the invention can thus be electrically neutral,positively charged, negatively charged or zwitterionic. The preferredcompounds are zwitterionic by virtue of a positively charged nitrogenatom in group (a)-(d) and a negatively charged carboxylate group (Yrepresents a negative charge).

The scope of R^(c) includes those groups suitable for attachment to ringcarbon and nitrogen atoms. Persons skilled in the art will readilyrecognize that a wide range of organic substituents are suitably used asR^(c). Persons skilled in the an will also recognize that somesubstituents, such as the --NR^(y) R^(z) substituents, are useful carbonsubstitution but not equally useful for nitrogen substitution.

Preferred R^(c) groups attached to ring carbon atoms are --NH₂, --SCH₃,--SOCH₃, --CH₂ OH, --(CH₂)₂ OH, --OCH₃, --COOM^(b), --CH₂ COOM^(b),--CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃, --SO₃ M^(b), --CH₂ SO₃M^(b), --CH₂ CH₂ SO₃ M^(b), --Br, --Cl, --F, --I, --CH₃, --CH₂ CH₃,--CH₂ CONH₂ and --CH₂ CON(C₁ -C₄ alkyl)₂ where M^(b) is defined above.

Preferred R^(c) groups attached to ring nitrogen atoms are --CH₂ OH,--(CH₂)₂ OH, --CH₂ COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂SCH₃, --CH₂ SO₃ M^(b), --CH₂ CH₂ SO₃ M^(b), --CH₃, --CH₂ CH₃, --CH₂CONH₂ and --CH₂ CON(C₁ -C₄ alkyl)₂ where M^(b) is defined above.

Preferred A spacer moieties include --CH₂ --, --CH₂ --CH₂ --, --CH₂--CH₂ --CH₂ --, --CH₂ --CH₂ --CH₂ --CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --,--SO₂ CH₂ --, --SCH₂ CH₂ --, --SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂CH₂ --, --N(CH₃)CH₂ CH₂ --, --CH₂ N(CH₃)CH₂ CH₂ --, --CONHCH₂ CH₂ --,--SO₂ NHCH₂ CH₂ --, --COCH₂ --, --CH═CHCH₂ -- and --CH₂ OCH₂ CH₂ --.Preferably, where Q is O, S, NH or N(C₁₋₄ alkyl), then r plus s is 2-6.

Preferred --A'-- groups include the preferred groups listed for A above.Further, A' may represent --O--, --S--, --NH--, --SO₂ --, --SO₂ NH--,--CONH--, --CH═CH--, --CH₂ S--, --CH₂ NH--, --CONHCH₂ -- or --SO₂ NHCH₂--.

In X, when X represents S(O)_(x), the preferred value of x is zero, andwhen X represents NR', the preferred value of R' is H.

In R^(a) and W, when these variables represent alkoxy substituted withR^(q), the preferred R^(q) values are --OH, --OCH₃, --CF₃ and --CO₂M^(a). In --COOM^(a), the preferred values of M^(a) are H and methyl.

When R^(a) or W represents --OC(O)R^(s), the preferred R^(s) values areC₁₋₄ alkyl and substituted C₁₋₄ alkyl.

When R^(a) or W represents --OC(O)NR^(y) R^(z), the preferred R^(y) andR^(z) values are H, lower alkyl and C₄₋₅ alkylidene.

When R^(a) or W represents --S(O)_(x) --R^(s), x preferably is zero, andR^(s) is preferably alkyl.

When R^(a) or W represents --SO₂ NR^(y) R^(z), R^(y) and R^(z)preferably represent H, lower alkyl or are taken together to represent aC₄₋₅ alkylidene group.

When R^(a) or W represents --N(R^(t))C(O)H, --N(R^(t))C(O)C₁₋₄ alkyl orsubstituted alkyl, --N(R^(t))C(O)OC₁₋₄ alkyl or substituted alkyl,--N(R^(t))C(O)NR^(y) R^(z) or --NR^(t) SO₂ R^(s), the preferred R^(t)groups are H and C₁₋₄ lower alkyl.

When R^(a) or W represents a C₅₋₇ cycloalkyl group where one carbon isreplaced with a heteroatom, --NH--, O, or --S(O)_(x) --, the preferredheteroatom is nitrogen, either --NH-- or --N(C₁₋₄ alkyl)--.

When R^(a) or W represents an alkenyl group, the preferred alkenyl groupis allyl, --CH₂ CH═CH₂.

Among the more preferred R^(a) groups are C₁₋₄ alkyl mono-substitutedwith hydroxy, such as, hydroxymethyl; formyl; carbamoyl, such as,--CONH₂ ; cyano; halo, such as iodo; C₁ to C₄ alkylthio, such asmethylthio and its dioxides, such as --SO₂ CH₃ ; and mono substituted C₂to C₄ alkylthio, such as hydroxyethylthio, --SCH₂ CH₂ OH.

In addition to the above, examples of the more preferred R^(a) and Wgroups include:

    ______________________________________                                        --OCH.sub.3                                                                   --OCH.sub.2 CH.sub.2 OH                                                                         --OCH.sub.2 CO.sub.2 Me                                     --F               --CF.sub.3                                                  --Br              --Cl                                                        --OH              --I                                                         --OCONH.sub.2     --OCOCH.sub.3                                               --SOCH.sub.3      --SCH.sub.3                                                 --SCH.sub.2 CH.sub.2 OH                                                                         --SO.sub.2 CH.sub.3                                         --SO.sub.2 NH.sub.2                                                                             --SOCH.sub.2 CH.sub.2 OH                                    --NHCHO           --SO.sub.2 N(CH.sub.3).sub.2                                --NHCO.sub.2 CH.sub.3                                                                           --NHCOCH.sub.3                                              --CN              --NHSO.sub.2 CH.sub.3                                       --COCH.sub.3      --CHO                                                       --CH--NOH         --COCH.sub.2 OH                                             --CH═NOCH.sub.2 CO.sub.2 Me                                                                 --CH═NOCH.sub.3                                         --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                                 --CH═NOCMe.sub.2 CO.sub.2 Me                            --CH═NOCMe.sub.2 CO.sub.2 Me                                                                --CO.sub.2 CH.sub.2 CH.sub.2 OH                             --CONH.sub.2      --CONHCH.sub.3                                              --CON(CH.sub.3).sub.2                                                                           --CONHCH.sub.2 CN                                           --CONHCH.sub.2 CONH.sub.2                                                                       --CONHCH.sub.2 CO.sub.2 Me                                  --CONHOH          --CONHCH.sub.3                                              tetrazolyl        --CO.sub.2 Me                                               --SCF.sub.3       --PO.sub.3 HMe                                              --CONHSO.sub.2 Ph --CONHSO.sub.2 NH.sub.2                                     --SO.sub.3 Me     --SO.sub.2 NHCN                                             --SO.sub.2 NHCONH.sub.2                                                                         --CH═CHCN                                               --CH═CHCONH.sub.2                                                                           --CH═CHCO.sub.2 Me                                      --Cbn,4 C--CONH.sub.2                                                                           --Cbn,4 C--CN                                               --CH.sub.2 OH     --CH.sub.2 N.sub.3                                          --CH.sub.2 CO.sub.2 Me and                                                                      --CH.sub.2 I.sub..                                          ______________________________________                                    

Listed below are the more preferred compounds of the invention. Thefollowing numbering system applies: ##STR29## wherein the representationof Ra includes attachment in either aromatic ring, at positions 1', 5',6', 7' or 8'. The most preferred compounds of the invention include thefollowing:

Compounds where m and n represent 1; m represents 1 and n representszero; and m represents 2 and n represents zero;

X represents a bond, --O--, --S--, --SO₂ --, --C(O)--, --NH--, --CH═CH--and --C(O)NH--;

Z and Z' represent --C(O)-- and a bond, respectively; --S-- and a bond,respectively; --SO₂ -- and a bond, respectively; --O-- and a bond,respectively; --NH-- and a bond, respectively; --OC(O) and a bond,respectively, and --(O)CO-- and a bond, respectively;

Y represents a negative charge and R^(a) is selected from: ##STR30##

The compounds of the invention can be synthesized in accordance with thefollowing general schemes and examples. ##STR31##

The syntheses of compounds I are outlined in Schemes I, II, and III,which depict strategies that progress from the most general to the morespecific. Basically, the skeletal arrangement of these molecules can beassembled in three key stages. Initially, the known, appropriatelysubstituted acetoxyazetidinone is reacted with a cycloalkanonylaromaticcompound in the presence of a tertiary amine base such as triethylamine,diisopropylethylamine, pyridine or the like, and a silylating agent suchas trimethylsilyltrifluoromethanesulfonate, in a solvent such asdichloromethane, acetonitrile or the like, at a temperature of from -23°C. to ambient temperatures, for from 1 to 24 hours, in an inertatmosphere. The reaction is such that the cycloalkanone is converted insitu to its corresponding silylenolether derivative, which in turnreacts with the activated form of the azetidinone, brought about by theinteraction of the acetoxyazetidinone with a relatively small percentageof the trimethylsilyltrifluoromethanesulfonate, to form a carbon-carbonbond from C-4 of the azetidinone to the alpha carbon of thecycloalkanone. The latter constitutes a new stereocenter in the adduct,and the ratio of the resulting diastereomers is typically almost equal.The isomers maybe separated by standard techniques and processedindividually. Alternatively, the silylenolether derivative of thecycloalkanone may be produced in a separate operation and then broughtinto interaction with the acetoxyazetidinone derivative and anactivating agent or Lewis acid such astrimethylsilyltrifluoromethanesulfonate, zinc chloride, zinc iodide,borontrifluoride etherate, stannous chloride, tin triflate, titaniumtrichloride, aluminium chloride or the like, in aprotic solvents such asdichloromethane, acetonitrile, benzene, THF, hexane or the like. In thisway, the stereochemical outcome of the reaction maybe altered to producea predominance of one isomer or the other.

The second key stage is the conversion of the newly formed azetidinoneto the corresponding Wittig intermediate via the "oxalimide process".This conversion is accomplished in two steps and begins with thereaction of the azetidinone and the known, appropriately protectedchlorooxalylester reagent, in the presence of a suitable base such aspyridine, triethylamine or the like, in an inert solvent such adichloromethane, toluene, or the like, from a temperature of from -23°C. to ambient temperatures, for from a few minutes to several hours.Typically the oxalimide which is rapidly formed is isolated byconventional techniques and may be similarly purified or, moreconveniently, used directly in the second step of the process. Here theoxalimide is heated with a large excess (10-20 equivalents) of analkoxyphosphine reagent such as triethoxyphosphine,diethoxymethylphosphine, or the like, in an inert solvent such asbenzene, toluene, xylene, or the like, at a temperature of from 50° C.to 120° C. for from a few minutes to several hours. The resultingalkoxyphosphorane intermediate is typically not isolated due to itshydrolytic lability, but instead can be used in situ in the final stageof the synthesis.

The last key stage involves the thermal cyclization of thealkoxyphosphorane intermediate in an inert solvent such as benzene,toluene, xylene or the like, at refluxing temperatures, in an inertatmosphere of nitrogen or helium, in the presence of a trace ofhydroquinone, for from an hour to five days.

At this juncture, the remaining number of steps to complete thesynthesis of the compounds I of the invention may vary. In cases where ahydroxyl group is present in the group at C-6 of the carbapenem nucleusor on the aromatic C-2 appendage, and it is covered with a protectinggroup (PG), the protecting group(s) maybe removed by establishedmethods, which are discussed further below. In this instance, and inexamples requiring no further chemistry at this stage, the carboxylprotecting group is analogously removed to affect the formation of I.Examples of this procedure am outlined in Schemes I and II. On the otherhand, prior to the removal of the carboxyl protecting group, additionalchemistry maybe performed which allows for the introduction offunctionality consistent with the scope of the invention. For example,Scheme III depicts a chemoselective activation of a benzylic typehydroxyl group and subsequent displacement with nucleophiles, describedherein, to generate penultimate intermediates to the desired I. Thisprocess is further detailed below.

Other examples of chemical transformations which can be implemented atthe carbapenem stage of the synthesis provide for certain definitions ofX and Z, including, e.g., oxidation at a sulfur atom to provide eitherthe corresponding sulfoxide or sulfone.

The starting materials for the initial stage of the foregoing sequenceare either known in the art or can be readily prepared by establishedmethods. In this regard the following references may be applicable:

5-phenyl-1-tetralone: K. Itoh, etal, Chem. Pharm. Bull., 32, 130 (1984);6-phenyl-1-tetralone: K. Itoh, etal, ibid.; M. S. Newman and H. V. Zahm,J. Amer. Chem. Soc., 65, 1097 (1943); N. L. Allinger and E. S. Jones, J.Org. Chem., 27, 70 (1962); 7-phenyl-1-tetralone: R. Buckle, etal, J.Medicinal Chem., 20, 1059 (1977); M. Weizmann, etal, Chemistry andIndustry, 402 (1940); A. R. Katritzky and C. M. Marson, J. Chem. Soc.,Perkin II, 1455 (1983); 7-bromo-1-tetralone: L. F. Fieser and A. M.Seligman, J. Amer. Chem. Soc., 60, 170 (1938); 6-amino-1-tetralone: N.L. Allinger and E. S. Jones, supra.

For syntheses involving the Suzuki reaction, see A. Suzuki, et al, Syn.Comm., 11, 513 (1981); and related chemistry: Wiley, P. F., J. Amer.Chem. Soc., 73, 4205 (1951); Flemming, W., etal, Chem. Ber., 58, 1612(1925); N. Miyaura, T. Yanagi, and A. Suzuki, Syn. Comm., 11, 513(1981); V. Snieckus, etal, J. Org. Chem., 56, 3763 (1991); V. N.Kalinin, Synthesis, 413, (1992); V. Snieckus, etal, Tet. Letters, 29,5459 (1988); V. Snieckus and M. A. Siddiqui, ibid, 5463 (1988).

For coupling to a known azetidinone to the side chain using Lewis acidcatalysis, see, e.g., A. G. M. Barrett & P. Quayle, J. Chem. Soc. Chem.Comm. 1076 (1981); Reider, P. J., et al. Tet. Let. 23, 2293 (1982);Hirai, K. et al. Heterocycles 17, 201 (1982); R. P. Artrill, A./G. M.Barrett, P. Quayle, J. Van der Westhuizen & M. J. Belts, J. Org. Chem.49, 1679 (1984)

The synthesis, substitution and elaboration of dibenzofurans anddibenzothiophenes has been well reviewed in the literature: M. V.Sargent & P. O. Stransky, Adv. Heterocycl. Chem. 35, 1-81 (1984); W. E.Parham Heterocyclyl. Comp., 2, 123 (1951); R. Livingstone in Rodd'sChemistry of Carbon Compounds, 2d ed. Vol. IV Part A, HeterocyclicCompounds, 194-202 (1973); F. M. Dean and M. V. Sargent in ComprehensiveHeterocyclic Chemistry, Vol. 4, Part 3, 599 (1979); J. Ashby & C. C.Cook, Adv. Heterocycl. Comp. 2, 164 (1951); R. Livingstone in Rodd'sChemistry of Carbon Compounds, 2d ed., Vol. IV, Part A, HeterocyclicCompounds, 300-305 (1973); S. Rajappa in Comprehensive HeterocyclicChemistry, Vol. 4, Part 3, 741 (1979); E. Campaigne, ibid., 863 (1979).

In Scheme V, the hydroxymethyl precursor substituent may be elaboratedinto the desired substituent group by converting the hydroxyl into anactive leaving group such as an iodide (giving --A--I), followed byreaction with a desired nitrogen containing aromatic compound. Moreparticularly, two alternative procedures may be utilized to produce aleaving group on the moiety --A-- and subsequently to replace such aleaving group with the desired substituent.

For the first procedure, the hydroxyl group of --A--OH may be convenedto a methanesulfonate group by treating with methanesulfonyl chloride(MsCl) in the presence of triethylamine. A suitable solvent, e.g.,dichloromethane, is employed and the reaction is carried out at reducedtemperatures. In turn, the methanesulfonate intermediate may beconverted to the reactive iodide derivative by treatment with sodiumiodide in a suitable solvent, e.g., acetone, at reduced or ambienttemperatures. Alternatively, the hydroxyl group may be directly convenedinto the iodide group by common methods known to the art. For example,treatment of the hydroxyl group with methyl triphenoxyphosphonium iodidein a suitable solvent, such as dimethylformamide, at reduced or ambienttemperatures, directly provides the desired iodide. Once the iodide hasbeen formed, the introduction of the desired substituent is accomplishedsimply by treating the iodide with the desired nitrogen containingcompound, e.g. a heteroaromatic compound such as pyridine. The reactionwill proceed in a suitable solvent, such as acetonitrile, at or aboutroom temperature. This displacement reaction may also be facilitated bythe addition of excess silver trifluoromethanesulfonate to the reactionmixture, in which case reduced temperatures are often desirable.

In a second procedure, the hydroxyl group of --A--OH may be convertedinto the reactive trifluoromethanesulfonate (triflate) group (SchemeIV). However, such an activating group cannot be isolated byconventional techniques but may be formed and used in situ. Thus,treatment of the hydroxyl group with a slight excess oftrifluoromethanesulfonic (triflic) anhydride in the presence of ahindered, non-nucleophilic base such as 2,6-lutidine, 2,4,6-collidine,or 2,6-di-tert-butyl-4-methyl- pyridine in a suitable solvent, such asdichloromethane, at reduced temperatures provides for the generation ofthe triflate activating group. Introduction of the desired group is thenaccomplished by reacting the above triflate in situ with the desirednitrogen containing compound at reduced temperature.

In certain cases it is possible and desirable to use the reactivenitrogen containing compound as the base for the formation of thetriflate activating group. In this case, treatment of the hydroxyl groupwith triflic anhydride in the presence of at least two equivalents ofthe reacting nitrogen compound under the conditions described aboveprovides the desired N-containing substituent.

Where the N ring contains substitution with a substituent R^(c), themost facile method of providing such a substituent is to employ as thereactant in the preparation methods described above a nitrogencontaining compound which already has the desired R^(c) substituent inplace. Such substituted compounds are readily available startingmaterials or may be prepared in a straightforward manner using knownliterature methods.

In one suggested synthesis, the hydroxyl may be converted to a reactiveleaving group such as iodo, which is then reacted in a nucleophilicdisplacement reaction with a nitrogen containing aromatic compound whichhas a nucleophilic side-chain substituent such as CH₂ SH or CH₂ NH₂. Inthis displacement reaction, it is the side-chain substituent that is thereacting nucleophile and not the aromatic ring nitrogen. Suitablesubstrates for this reaction include 2-(mercaptomethyl)pyridine,2-aminopyridine, 2-(aminomethyl)pyridine or 4-(mercaptomethyl)-pyridine. The reaction is carried-out in an inert organic solvent, e.g.methylene chloride, at from about 0° C. to room temperature in thepresence of a non-nucleophilic base such as triethylamine ordiisopropylethylamine.

A second suggested synthesis starting from a precursor A'--OH (e.g.hydroxymethyl) consists of oxidation of the alcohol functionally to analdehyde followed by Wittig-type olefination with an appropriatenitrogen-containing aromatic substituted reagent. The oxidation may beconveniently accomplished by a Swern oxidation employing oxalylchloride-dimethylsulfoxide followed by triethylamine. The reaction isconducted in methylene chloride as a solvent at from -70° C. to 0° C.The Wittig reaction is carried-out by reacting the aldehyde with thedesired Wittig reagent in a polar solvent such as acetonitrile ordimethylsulfoxide at about room temperature. Suitable Wittig reagentsinclude: pyridylmethylenetriphenylphosphorane,quinolylmethylenetriphenylphosphorane andthiazolylmethylenetriphenylphosphorane. Depending on the particularR^(a) group desired, many other synthesis schemes may be employed, aswould be apparent to an organic chemist skilled in the art.

Compounds where R^(a) represents type (c) may be prepared in ananalogous manner to that described for type (a) substituents, exceptthat the nitrogen containing compound employed in the displacementreaction is an aliphatic amine (i.e. NR^(y) R^(z)). In cases where theamino group is directly bonded to the ring nucleus (i.e. --A_(p) NR^(y)R^(z) where p=O) the amine is most conveniently attached to the ringstructure prior to its incorporation into the carbapenem system.

If such an amine is primary or secondary, it may require protection witha suitable amine protecting group during the steps employed to attachthe ring structure to the carbapenem. Tertiary amines typically requireno protection.

Compounds where R^(a) represents (d) may be prepared by reacting thecompound A'p--S--L (Leaving Group) with an N containing ring, prior toconnection to the carbapenem. In the preparation methods describedabove, the carboxyl group at the 3-position and the hydroxyl group atthe 8-position of the preferred carbapenem remain blocked by protectinggroups until the final product is prepared. Deblocking may be carriedout in a conventional manner. For compounds prepared according to theFlow Sheets, below deprotection may be carried out first by desilylationusing tetrabutylammonium fluoride and acetic acid and second bydeallylation using a palladium catalyzed reaction in a solutioncontaining potassium 2-ethylhexanoate or, alternatively, anothersuitable nucleophile such as pyrrolidine. Alternatively, deprotectionmay be conducted sequentially. Thus, the protected precursor compound isexposed initially to aqueous acidic conditions, acetic acid or diluteHCl or the like, in an organic solvent such as tetrahydrofuran at 0° C.to 50° C. for from a few minutes to several hours. The resultingdesilylated carbapenem may be isolated by conventional techniques, butis more conveniently taken into the final deprotection process. Thus,addition of an inorganic base such as NaHCO₃ or KHCO₃ or buffer such assodium phosphate and 10% Pd/C followed by hydrogenation provides for theremoval of the p-nitrobenzyl protecting group and the formation of thefinal compound of Formula I.

The carbapenem compounds of the present invention are use per se and intheir pharmaceutically acceptable salt and ester forms in the treatmentof bacterial infections in animal and human subjects. The term"pharmaceutically acceptable ester, salt or hydrate," refers to thosesalts, esters and hydrated forms of the compounds of the presentinvention which would be apparent to the pharmaceutical chemist. i.e.,those which are substantially non-toxic and which may favorably affectthe pharmacokinetic properties of said compounds, their palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof the raw materials, ease of crystallization, yield, stability,hygroscopicity, and flowability of the resulting bulk drug.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds.

The pharmaceutically acceptable salts referred to above may take theform --COOY. The Y may be an alkali metal cation such as sodium orpotassium. Other pharmaceutically acceptable cations for Y may becalcium, magnesium, zinc, ammonium, or alkylammonium cations such astetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium,meglumine, triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above may also includenon-toxic acid addition salts. Thus, the Formula I compounds can be usedin the form of salts derived from inorganic or organic acids. Includedamong such salts are the following: acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalare, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.

The pharmaceutically acceptable esters of the present invention are suchas would be readily apparent to a medicinal chemist, and include, forexample, those described in detail in U.S. Pat. No. 4,309,438. Includedwithin such pharmaceutically acceptable esters are those which arehydrolyzed under physiological conditions, such as pivaloyloxymethyl,acetoxymethyl, phthalidyl, indanyl and methoxymethyl, and othersdescribed in detail in U.S. Pat. No. 4,479,947. The esters which arehydrolizable under physiological conditions am also referred to as"biolabile esters". Many biolabile esters have oral activity, protectingthe drug from excessive acid degradation upon oral administration.

Some of the groups which Y represents form biolabile esters with thecarboxylate to which Y is attached. Biolabile exters are biologicallyhydrolizable, and many am suitable for oral administration, due to goodabsorption through the stomach or intenstinal mucosa, resistance togastric acid degradation and other factors. Examples of biolabile estersinclude compounds in which Y represents an alkoxyalkyl,cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl, alkoxyaryl,alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl, arylthioalkyl oralkylthioaryl group. All of these groups can be substituted in the alkylor aryl portions thereof with acyl or halo groups. The following Yspecies are preferred as biolabile ester forming moieties.:acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl,1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

Some of the novel carbapenem compounds of the present invention take theform COOY, where Y is a readily removable carboxyl protecting group.Such conventional groups consist of known groups which are used toprotectively block the carboxyl group during the synthesis proceduresdescribed therein. These conventional blocking groups are readilyremovable, i.e., they can be removed, if desired, by procedures whichwill not cause cleavage or other disruption of the remaining portions ofthe molecule. Such procedures include chemical and enzymatic hydrolysis,treatment with chemical reducing or oxidizing agents under mildconditions, treatment with a transition metal catalyst and a nucleophileand catalytic hydrogenation. Examples of such ester protecting groupsinclude benzhydryl, p-nitrobenzyl, 2-naphthylmethyl, allyl, benzyl,trichloroethyl, silyl such as trimethylsilyl or trimethylsilylethyl,phenacyl, p-methoxybenzyl, acetonyl, o-nitrobenzyl, p-methoxyphenyl,4-pyridylmethyl, and t-butyl.

Likewise, the hydroxy group at position 8 can be protected asappropriate to facilitate the syntheses described herein.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and to a lesser extentGram-negative bacteria, and accordingly find utility in human andveterinary medicine. The antibacterials of the invention are not limitedto utility as medicaments; they may be used in all manner of industry,for example: additives to animal feed, preservation of food,disinfectants, and in other industrial systems where control ofbacterial growth is desired. For example, they may be employed incompositions in concentrations ranging from about 0.01 to about 100parts of antibiotic per million parts of solution in order to destroy orinhibit the growth of harmful bacteria on medical and dental equipmentand as bactericides in industrial applications, for example in waterbased paints and in the white water of paper mills to inhibit the growthof harmful bacteria.

Many of compounds of the present invention are biologically activeagainst MRSA/MRCNS. This is demonstrated below using the followingbiological activity protocol.

In vitro antibacterial activity determined in accordance with theprotocol set forth below is predictive of in vivo activity, when thecompounds are administered to a mammal infected with a susceptiblebacterial organism.

Minimum inhibitory concentrations for different compounds may becalculated using the procedures set forth in Lorian, V. (ed.)Antibiotics in Laboratory Medicine (3rd ed.) pages 30-35 if desired.However, by comparing disc sensitivities to a known compound, e.g.,imipenem, this calculation is not required to recognize MRSA/MRCNSactivity.

Assay Used to Test the Activities of Carbapenems AgainstMethicillin-Resistant Staphylococci: The assay is an antibioticdisc-diffusion assay modeled after the method described by Bauer andKirby, et al.1, with the following modifications and clarifications:

Agar: This assay employs an agar depth of 2 mm instead of 4 mm.

Zone Readings: The inner, completely clear zone is measured.

Culture Storage: Frozen vials of strains are stored at -80° C. Workingslants are prepared from frozen vials and are used for 1 month to 6weeks. For methicillin-resistant2 strains the slant medium is MulellerHinton Agar; for control strains the slant medium is Brain HeartInfusion Agar. After inoculation from frozen vials,methicillin-resistant slant cultures are incubated at 28° C. until goodgrowth is achieved (approximately 20 hours); slants of control strainsare incubated at 37° C. for 16-18 hours.

Preparation of Control Inocula for Assay: Pipet 2 ml Brain HeartInfusion Broth (BHIB) into a sterile, plastic 17×100 mm tube. Use asterile cotton tipped applicator to pick up a very small amount ofculture from the slant and twirl it in the BHIB to achieve a light butvisible inoculum (approximately 1×106-107 cuf/ml). Incubate at 37° C.and 220 rpm for 17-18 hours.

Preparation of Methicillin-Resistant Inocula for Assay: Formethicillin-resistant strains, inoculate 0.5 ml of BHIB heavily (toachieve approximately 1×108-109 cfu/ml) from the slant culture by usinga sterile cotton tipped applicator. With the applicator spreadapproximately 0.1 ml of the suspension onto the surface of a 15×100 mmpetri plate containing 10 ml Mueller Hinton Agar. Incubate the plate at30° C. for approximately 18 hours.

Inoculum Adjustment: The 17-18 hour control Staphylococci cultures arediluted 100× in phosphate-buffered saline (PBS).

Methicillin-resistant Staphylococci: With a cotton tipped applicator,swab enough growth off the grown plates into 1 ml BHIB to achieve avisual concentration of approximately 1×109 cfu/ml. Mix vigorously anddilute in PBS so that dilutions appear visually to be slightly moreconcentrated than the 100× diluted control cultures. Measure %transmission (% T) at 660 nm in a Spectronic 20 or otherspectrophotometer. Add measured quantities of PBS to dilutions toachieve % T @ 1% above or below the % T measurement for the controlcultures. Make sterile dilutions using the same proportions.

Plate Incubation Following Plate Inoculation and Disc Placement:Incubate control plates for 18 hours at 37° C. Incubatemethicillin-resistant Staphylococci plates for 18 hours at 30° C.

The compounds of this invention may be used in a variety ofpharmaceutical preparations. They may be employed in powder orcrystalline form, in liquid solution, or in suspension. They may beadministered by a variety of means; those of principal interest include:topically, orally and parenterally by injection (intravenously orintramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Theinjectable compositions may take such forms as suspensions, solutions,or emulsions in oily or aqueous vehicles, and may contain formulatingagents. Alternatively, the active ingredient may be in powder(lyophillized or non-lyophillized) form for reconstitution at the timeof delivery with a suitable vehicle, such as sterile water.

Topical applications may be formulated in hydrophobic or hydrophilicbases as ointments, creams, lotions, paints, or powders.

Oral compositions may take such forms as tablets, capsules, oralsuspensions and oral solutions. The oral compositions may utilizeconventional formulating agents, and may include sustained releaseproperties as well as rapid delivery forms.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated, the route and frequencyof administration, the sensitivity of the pathogen to the particularcompound selected, the virulence of the infection and other factors.Such matters, however, are left to the routine discretion of thephysician according to principles of treatment well known in theantibacterial arts. Another factor influencing the precise dosageregimen, apart from the nature of the infection and peculiar identity ofthe individual being treated, is the molecular weight of the compound.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from about 0.01% to as high as about 99% of activematerial, the preferred range being from about 10-60%. The compositionwill generally contain from about 15 mg to about 2.5 g of the activeingredient; however, in general, it is preferable to employ a dosageamount in the range of from about 250 mg to 1000 mg. In parenteraladministration, the unit dosage will typically include the pure compoundin sterile water solution or in the form of a soluble powder intendedfor solution, which can be adjusted to neutral pH and isotonic.

The preferred methods of administration of the Formula I antibacterialcompounds include oral and parenteral, e.g., i.v. infusion, i.v. bolusand i.m. injection.

For adults, about 5-50 mg of Formula I antibacterial compound per kg ofbody weight given one to four times daily is preferred. The preferreddosage is 250 mg to 1000 mg of the antibacterial given one to four timesper day. More specifically, for mild infections a dose of about 250 mgtwo or three times daily is recommended. For moderate infections againsthighly susceptible gram positive organisms a dose of about 500 mg threeor four is recommended. For severe, life-threatening infections againstorganisms at the upper limits of sensitivity to the antibiotic, a doseof about 1000-2000 mg three to four times daily may be recommended.

For children, a dose of about 5-25 mg/kg of body weight given 2, 3, or 4times per day is preferred; a dose of 10 mg/kg is typically recommended.

The compounds of Formula I are of the broad class known as carbapenems.Many occurring carbapenems are susceptible to attack by a renal enzymeknown as dehydropeptidase (DHP). This attack or degradation may reducethe efficacy of the carbapenem antibacterial agent. The compounds of thepresent invention, on the other hand, are less subject to such attack,and therefore may not require the use of a DHP inhibitor. However, suchuse is optional and contemplated to be part of the present invention.Inhibitors of DHP and their use with carbapenems are disclosed in, e.g.,[European Patent Application Nos. 79102616.4, filed Jul. 24, 1979(Patent No. 0 007 614); and 82107174.3, filed Aug. 9, 1982 (PublicationNo. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. The cited European Patent Applications define the procedurefor determining DHP susceptibility of the present carbapenems anddisclose suitable inhibitors, combination compositions and methods oftreatment. A preferred weight ratio of Formula I compound: DHP inhibitorin the combination compositions is about 1:1.

A preferred DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid or a useful salt thereof.

The invention is further described in connection with the followingnon-limiting examples.

PREPARATIVE EXAMPLE 1 Preparation of Tetralone Derivative ##STR32##

The 7-bromo-1-tetralone (2.07 g, 9.21 mmole), the boronic acidderivative(5.4 g, 13.8 mmole), from exampletetrakistriphenylphosphinepalladium (531 mg, 0.46 mmole), and 8.4mL(16.8 mmole) of a 2.0M aqueous solution of sodium carbonate werecombined and stirred in 20 mL of toluene and 10 mL of ethanol at refluxfor 3 hour. The cooled mixture was partitioned between diethyl ether andwater and the organic phase was separated, washed with brine, dried overanhydrous sodium sulfate, filtered, and evaporated. Purification bycolumn chromatography on silica gel eluted with dichloromethane-pet.ether(1:1) gave 4.53 g (100%) of the product.

¹ H NMR(CDCl₃) δ: 1.12(s, 9H), 2.18(p, J=6 Hz, 2H), 2.71(t, J=6 Hz, 2H),3.02(t, J=6 Hz, 2H), 7.32-7.76(m, 16H), and 8.3(d, J=2 Hz, 1H).

PREPARATIVE EXAMPLE 2 Preparation of Tetralone Stannane ##STR33##

The 7-bromo- 1-tetralone (225 mg, 1.0 mmole), 655.2 mg (2.0 mmole) ofhexamethylditin, tetrakistriphenylphosphinepalladium (57.7 mg, 0.05mmole), and 26.2 mg(0.1 mmole) of triphenylphosphine were combined andstirred in 3 mL of toluene at 100° C. for 1 hour. The cooled mixture waspartitioned between ethyl acetate and ice-water and the organic phasewas separated, washed with brine, dried over anhydrous sodium sulfate,filtered, and evaporated. Purification by plate-layer chromatography onsilica gel eluted with dichloromethane-pet. ether(2:1) gave 307.2mg(99%) of the stannane.

¹ H NMR(CDCl₃) δ: 0.16-0.44(m, 9H), 2.16(p, J=6 Hz, 2H), 2.69 (t, J=6Hz, 2H), 2.95(t, J=6 Hz, 2H), 7.22(d, J=7.9 Hz, 1H), 7.6(dd, J=1.2 and7.9 Hz, 1H), and 8.16(bs, 1H).

PREPARATIVE EXAMPLE 3 Preparation of Tetralone Derivative ##STR34##

The 7-trimethylstannyl- 1-tetralone (294.1 mg, 0.95 mmole), 262.8mg(0.95 mmole ) of ethyl-2-iodo-benzoate, 19.8 mg(0.02 mmole)trisdibenzylideneacetonedipalladium-chloroform catalyst and 144.5 mg(0.1mmole) of diisopropylammonium hydrochloride were combined and stirred in3 mL of N-methylpyrrolidinone at room temperature for 1.5 hour. Themixture was partitioned between diethyl ether and ice-water and theorganic phase was separated, washed twice with water and then brine,dried over anhydrous sodium sulfate, filtered, and evaporated.Purification by plate-layer chromatography on silica gel eluted withdichloromethane-pet. ether(3:1) gave 214.7 mg(77%) of the coupledproduct.

¹ H NMR(CDCl₃) δ: 1.11(t, J=7 Hz, 3H), 2.18(p, J=6 Hz, 2H), 2.65(t, J=6Hz, 2H), 3.02(t, J=6 Hz, 2H), 4.14(q, J=7 Hz, 2H),7.29-7.54(m, 5H),7.87(dd, J=1.9 and 6.7 Hz, 1H), and 8.0(d, J=1.9 Hz, 1H). IR(CH₂ Cl₂)cm⁻¹ : 1720 and 1683.

PREPARATIVE EXAMPLE 4 Preparation of Acid Tetralone Derivative ##STR35##

A stirred mixture of 197.6 mg (0.67 mmole) of the tetralone esterderivative and 282.1 μL (1.41 mmole) of 5N NaOH solution in 3 mL ofmethanol was stirred at ambient temperature for 16 hours, and thenrefluxed for 3 hours. The cooled mixture was concentrated in vacuo,diluted with water and extracted with ether. The separated aqueous layerwas acidified with 2N HCl and extracted with ether. The extract wasdried over anhydrous sodium sulfate, filtered, and evaporated to give112 mg (63%) of the tetralone acid derivative as a colorless foam.

¹ H NMR (CDCl₃) δ: 2.2 (p, J=6 Hz, 2H), 2.7 (t, J=6 Hz, 2H), 3.02 (t,J=6 Hz, 2H), 7.24-7.6 (m, 5H), 7.98 (m, 1H), and 8.04 (m, 1H).

PREPARATIVE EXAMPLE 5 Preparation of Cyclohexanonyl-fluoreneoneDerivative ##STR36##

A stirred mixture of 107 mg (0.4 mmole) of the tetralone acid derivativeand 1.5 g of polyphosphoric acid (PPA) in 3 mL of p-xylene was stirredat 130° C. for 0.5 hour. The mixture was cooled and the xylene decantedfrom the separated PPA phase. The PPA phase was dissolved in water andextracted with a mixture of ether and methylene chloride. The separatedorganic phase was washed with brine, dried over anhydrous sodiumsulfate, filtered, and evaporated. The dark red solid was purified bypreparative plate layer chromatography [one development methylenechloride] to give 41.6 mg (42%) of the product.

¹ H NMR (CDCl₃) δ: 2.12 (p, J=6 Hz, 2H), 2.75 (t, J=6 Hz, 2H), 2.89 (t,J=6 Hz, 2H), 7.23-7.65 (m, 6H). IR (CH₂ Cl₂) cm⁻¹ : 1721 and 1690.

PREPARATIVE EXAMPLE 6 Preparation of4-t-Butyldiphenylsiloxymethylbromopbenzene ##STR37##

To a stirred solution of 7.48 g (40 mmoles) of p-bromobenzyl alcohol and6.07 g (60 mmoles) of triethylamine in 70 mL of sieve dried DMF at 0° C.was added 14.3 g (52 mmoles) of neat t-butyldiphenylsilylchloride. Theice-water bath was removed and the mixture was stirred further for 20hours.

The mixture was partitioned between ether, ice-water, and 2Nhydrochloric acid, and the organic phase was separated, washed withwater and brine, dried over anhydrous sodium sulfate, filtered, andevaporated.

Purification by column chromatography on 200 g of EM-60 silica geleluting with hexanes-methylene chloride (3:1) gave 15.9 g (94%) of thetitle compound.

NMR (CDCl₃) δ: 1.1 (s, 9H), 4.72 (s, 2H), 7.22 (d, J=8.3 Hz, 2H), 7.43(m, 8H), 7.7 (m, 4H).

PREPARATIVE EXAMPLE 7 Preparation of4-t-butyldiphenylsiloxymethylphenylboronic acid ##STR38##

To a stirred solution of p-t-butylidiphenylsiloxymethylbromobenzene(10.1 g, 23.8 mmoles) in 100 mL of dry tetrahydrofuran at -78° C. undernitrogen was added dropwise 9.9 mL (25.0 mmoles) of 2.5M n-butyllithiumin hexane. The mixture was stirred at -78° C. for 15 minutes and 4.7 g(25.0 mmoles) of triisopropylborate was added. After 5 minutes, the lowtemperature bath was removed, and the mixture was stirred further for1.5 hours.

The mixture was poured onto ice-2N hydrochloric acid and ether wasadded. The biphasic mixture was stirred for 0.5 hour and the organicphase was separated, washed with brine, dried over anhydrous sodiumsulfate, filtered, and evaporated to give 8.8 g (94.2% of crudeproduct).

Precipitation from an ether-methylene chloride solution of the crudematerial with hexanes gave 7.1 g (76%) from two crops.

EXAMPLE 1 Preparation of Azetidinone 1 ##STR39##

To a stirred mixture of 3.68 g(12.7 mmole) of azetidinone, 4.26 g(19mmole) of 7-phenyltetralone, and 2.59 g(25.6 mmole) of triethylamine in50 mL of sieve dried dichloromethane at 0° C. was added 6.26 g(28.1mmole) of trimethylsilyl triflate. The resulting mixture was stirredunder an inert atmosphere of nitrogen at 0° C. for four hours. Themixture was partitioned between diethyl ether, ice-water, and 2Nhydrochloric acid. The organic phase was separated, washed with brineand then saturated sodium bicarbonate and sodium chloride, dried overanhydrous sodium sulfate, filtered, and evaporated.

The residue was purified by silica gel chromatography usingtoluene-diethyl ether(3:1) as eluant, to give 5.5 g(95%) of the productmixture 1. By a combination of crystallization and silica gelchromatography the individual α and β isomers were separated.

α-Isomer:

¹ H NMR(CDCl₃) δ: 0.08(s, 3H), 0.1(s, 3H), 0.9(s, 9H), 1.3(d, 3H),1.94(m), 2.34(m), 2.58(m), 2.86(m), 3.08(m), 3.76(dd, 1H), 4.22(p, 1H),6.54(bs, 1H), 7.28-7.8(m, 7H), and 8.22(d, 1H). IR(CH₂ Cl₂) cm-1: 3420,1755, 1660, and 1620. MS(m/e): 392[M+--C(CH₃)₃ ].

β-Isomer:

1H NMR(CDCl₃) δ: 0.1(s, 6H), 0.88(s, 9H), 1.28(d, 3H), 1.98-2.42(m, 2H),2.76(m, 1H), 3.1(m, 3H), 4.3(p, 1H), 4.48(t, 1H), 5.96(bs, 1H),7.3-7.8(m, 7H), and 8.22(d, 1H). IR(CH₂ Cl₂) cm-1: 3410, 1760, 1660, and1620. MS(m/e): 392[M+--C(CH₃)₃ ].

α and β isomers refer to the carbon atom attached to C-4 of theazetidinone ring.

EXAMPLE 1A Preparation of Azetidinones

In a manner analogous to Example 1, the following azetidinones wereprepared:

    __________________________________________________________________________                                                     .sup.1 H NMR SHIFT                                                            (δ)                                                               YIELDS                                                                              H-4                                                                     (%)   α-ISOMER                                                                       β-ISOMER         __________________________________________________________________________     ##STR40##                                 81    3.74   4.47                   ##STR41##                                 72    3.72   4.46                   ##STR42##                                 80    3.76   4.47                   ##STR43##                                 47    3.70   4.28                  __________________________________________________________________________     PG = Si(Me).sub.2 CMe.sub.3 -                                            

EXAMPLE 2 Synthesis of Oxalimide 2 ##STR44##

To a stirred solution of 449 mg(1 mmole) of β-isomeric azetidinone 1,from example 1, and 316.4 mg(4 mmole) of pyridine in 4 mL of sieve drieddichloromethane at 0° C. under an atmosphere of nitrogen was added 1.5mL of a 2M stock solution of allylchlorooxalate in dichloromethane. Theresulting mixture was stirred at 0° C. for 0.5 hour and then partitionedbetween diethyl ether, ice-water, and pH 7 phosphate buffer. The organicphase was separated, washed with brine, dried over anhydrous sodiumsulfate, filtered, evaporated, and dried in vacuo to provide 568 mg ofcrystalline solid 2.

¹ H NMR(CDCl₃) δ: 0.06(s, 6H), 0.85(s, 9H), 1.2(d, J=6.3 Hz, 3H),2.04-2.3(m, 2H), 3.1-3.3(m, 4H), 4.3(m, 1H), 4.68(t, J=3.4 Hz, 1H),4.8(m, 2H), 5.28-5.45(m, 2H), 5.9-5.99(m, 1H), 7.26-7.76(m, 7H), and8.28(bs, 1H). IR(CH₂ Cl₂) cm⁻¹ : 1810, 1752, 1680, and 1620.

EXAMPLE 3 Synthesis of Phosphorane 3 ##STR45##

The oxalimide 2 (567.4 mg, 1 mmole), from example 2, andtriethylphosphite(1.68 g, 10 mmole) in 5 mL p-xylene was stirred at 120°C. under an inert atmosphere of nitrogen for 1.5 hours. The cooledmixture was rotoevaporated under high vacuum and dried further in vacuoto provide a quantitative amount of phosphorane product 3, which wasused immediately without further purification.

EXAMPLE 4 Preparation of Carbapenem 4 ##STR46##

A stirred solution of phosphorane 3 (719.1 mg, 1 mmole), from Example 3,with a crystal of hydroquinone in 25 mL of p-xylene was kept at 140° C.under an atmosphere of nitrogen for 24 hours. The cooled solution wasevaporated and the residue purified by plate layer chromatography [onedevelopment pet. ether-ether(3:1)] to give 353 mg(66%) of 4 as a yellowfoam.

¹ H NMR(CDCl₃) δ: 0.097(s, 6H), 0.9(s, 9H), 1.27(d, J=6.1 Hz, 3H),1.94-2.1(m, 2H), 3.06-3.2(m, 3H), 3.25(dd, J=3.2 and 6.1 Hz, 1H), 4.3(m,1H), 4.32(dd, J=3.2 and 7.5 Hz, 1H), 4.7(m, 2H), 5.1-5.42(m, 2H),5.8-6.02(m, 1H), 7.16-7.6(m, 7H), and 8.0(d, J=1.5 Hz. 1H). IR(CH₂ Cl₂)cm⁻¹ : 1775 and 1718. UV(dioxane) nm: 326, 269. MS(m/e): 529(M⁺).

EXAMPLE 4A Preparation of Carbapenems

Using the procedures of examples 2, 3, and 4, the following quadracycliccarbapenems were prepared:

    __________________________________________________________________________                                  OVERALL                                                                              CYLIZATION                                                                            .sup.1 H NMR SHIFT                                                            (δ)                                                      YIELD (%)                                                                            TIME (HR)                                                                             H-5   H-8                        __________________________________________________________________________     ##STR47##                    33     20      4.38  7.88                        ##STR48##                    19     22      4.30  7.72                        ##STR49##                    27     20      4.33  8.02                        ##STR50##                    28     96      3.81  8.79                        ##STR51##                    14     66      3.81  8.61                        ##STR52##                     7     70      3.74  8.34                       __________________________________________________________________________     PG = Si(Me).sub.2 CMe.sub.3 -                                            

EXAMPLE 4B Preparation of Carbapenems

Using the procedures of examples 2, 3, and 4, the following hexacycliccarbapenems are prepared:

    __________________________________________________________________________     ##STR53##                                                                    m  n   X        Z      Z'  R.sup.a   Position R.sup.a                         __________________________________________________________________________    1  1   bond     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   bond     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          8'                                       1  1   bond     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          6'                                       1  zero                                                                              O        CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              S        CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              SO.sub.2 CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(OCH.sub.2).sub.2                                                                     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              NCO.sub.2 allyl                                                                        CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              CHCH     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   C(O)NH   CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       2  1   bond     CO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   bond     S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              O        S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              S        S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              SO.sub.2 SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(OCH.sub.2).sub.2                                                                     S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              NCO.sub.2 allyl                                                                        S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              CHCH     S      bond                                                                              CH.sub.2 OSiPh.sub. 2 CMe.sub.3                                                         7'                                       1  1   OCNH     S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       2  1   bond     S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   bond     SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              O        SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              SO.sub.2 S      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(O)NH   SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(OCH.sub.2).sub.2                                                                     SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              NCO.sub.2 allyl                                                                        SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              CHCH     SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   C(O)NH   SO     bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       2  1   bond     SO.sub.2                                                                             bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   bond     O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              O        O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              SO.sub.2 O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(O)NH   O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(OCH.sub.2).sub.2                                                                     O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              NCO.sub.2 allyl                                                                        O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              CHCH     O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   NHC(O)   O      bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       2  1   bond     OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  1   bond     OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              O        OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              S        OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(O)NH   OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              C(OCH.sub.2).sub.2                                                                     OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              NCO.sub.2 allyl                                                                        OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       1  zero                                                                              CHCH     OCO    bond                                                                              CH.sub.2 OSiPh.sub.2 CMe.sub.3                                                          7'                                       __________________________________________________________________________

EXAMPLE 5 Preparation of Carbapenem 5 ##STR54##

To a stirred solution of 4 (98.7 mg, 0.19 mmole) in 1 mL oftetrahydrofuran at room temperature under an atmosphere of nitrogen wasadded sequentially neat glacial acetic acid (39.2 mg, 0.65 mmole) and0.56 mL(0.56 mmole) of a 1M solution of tetrabutylammonium fluoride inTHF. The mixture was stirred at ambient temperature for 24 hours.

The mixture was partitioned between ethyl acetate, ice-water, andsaturated sodium bicarbonate solution and the organic phase wasseparated, washed with brine, dried over anhydrous sodium sulfate,filtered, and evaporated.

Purification by plate layer chromatography [one development CH₂ Cl₂-ether(3:1)] gave 45.1 mg(58%) of product 5.

¹ H NMR(CDCl₃) δ: 1.36(d, J=6.2 Hz, 3H), 1.94-2.2(m, 3H), 3.08-3.28(m,3H), 3.33(dd, J=3.2 and 6.6 Hz, 1H), 4.28(m, 1H), 4.36(dd, J=3.2 and 7.5Hz, 1H), 4.7(m, 2H), 5.1-5.4(m, 2H), 5.8-6.02(m, 1H), 7.12-7.6(m, 7H),and 8.0(d, J=1.5 Hz, 1H). IR(CH₂ Cl₂) cm⁻¹ : 3600, 1775 and 1720.UV(dioxane) nm: 326, 254. MS(m/e): 415(M⁺).

EXAMPLE 5A Preparation of Carbapenems

Following the procedure of example 5, the following quadracycliccarbapenems were prepared:

    __________________________________________________________________________                             YIELD                                                                              .sup.1 H NMR SHIFT (δ)                                             (%)  H-5   H-8                                       __________________________________________________________________________     ##STR55##               43   4.37  7.89                                       ##STR56##               53   4.34  7.72                                       ##STR57##               28   4.37  8.03                                       ##STR58##               53   3.85  8.72                                       ##STR59##               61   3.84  8.57                                      __________________________________________________________________________

EXAMPLE 5B Preparation of Carbapenems

Using the procedure of Example 5, the following hexacyclic carbapenemsare prepared:

    __________________________________________________________________________     ##STR60##                                                                                              Position                                            m n  X      Z     Z' R.sup.a                                                                            R.sup.a                                             __________________________________________________________________________    1 1  bond   CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  bond   CO    bond                                                                             CH.sub.2 OH                                                                        8'                                                  1 1  bond   CO    bond                                                                             CH.sub.2 OH                                                                        6'                                                  1 zero                                                                             O      CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             S      CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             SO.sub.2                                                                             CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(OCH.sub.2).sub.2                                                                   CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             NCO.sub.2 allyl                                                                      CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             CHCH   CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  C(O)NH CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  2 1  bond   CO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  bond   S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             O      S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             S      S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             SO.sub.2                                                                             SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(OCH.sub.2).sub.2                                                                   S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             NCO.sub.2 allyl                                                                      S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             CHCH   S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  C(O)NH S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  2 1  bond   S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  bond   SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             O      SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             SO.sub. 2                                                                            S     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(O)NH SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(OCH.sub.2).sub.2                                                                   SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             NCO.sub.2 allyl                                                                      SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             CHCH   SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  C(O)NH SO    bond                                                                             CH.sub.2 OH                                                                        7'                                                  2 1  bond   SO.sub.2                                                                            bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  bond   O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             O      O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             SO.sub.2                                                                             O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(O)NH O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(OCH.sub.2).sub.2                                                                   O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             NCO.sub.2 allyl                                                                      O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             CHCH   O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  NHC(O) O     bond                                                                             CH.sub.2 OH                                                                        7'                                                  2 1  bond   OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 1  bond   OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             O      OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             S      OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(O)NH OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             C(OCH.sub.2).sub.2                                                                   OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             NCO.sub.2 allyl                                                                      OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  1 zero                                                                             CHCH   OCO   bond                                                                             CH.sub.2 OH                                                                        7'                                                  __________________________________________________________________________

EXAMPLE 6 Preparation of Carbapenem Derivative 6 ##STR61##

To a stirred solution of 22.6 mg(0.05 mmole) of diol in 0.5 ml ofmethylene chloride at -23° C. under nitrogen was added sequentially 8.8mg(0.1 mmole) of N-methylimidazole and then 15 mg(0.053 mmole) oftriflic anhydride. The resulting mixture was stirred further for 3hours. The mixture was partitioned between methylene chloride and water,and the organic phase separated, dried over anhydrous sodium sulfate,filtered, and evaporated. The residue was dissolved in a minimum amountof methylene chloride and the product was precipitated by the additionof diethyl ether; repetition, and drying in vacuo gave 24.6 mg(86%) of6.

¹ H NMR(CDCl₃ -d₆ -Acetone) δ: 1.2(d, CH₃), 3.8(s, N--CH₃), and 9.1(bs).

EXAMPLE 6A Preparation of Carbapenems

Using the procedure of example 6, the following hexacyclic carbapenemsare prepared:

    __________________________________________________________________________     ##STR62##                                                                    m n  X      Z   Z' R.sup.a         Position R.sup.a                           __________________________________________________________________________    1 1  bond   CO  bond                                                                              ##STR63##      7'                                         1 1  bond   CO  bond                                                                              ##STR64##      8'                                         1 1  bond   CO  bond                                                                              ##STR65##      7'                                         1 1  bond   CO  bond                                                                              ##STR66##      7'                                         1 1  bond   CO  bond                                                                              ##STR67##      7'                                         1 1  bond   CO  bond                                                                              ##STR68##      7'                                         1 1  bond   CO  bond                                                                              ##STR69##      7'                                         1 1  bond   CO  bond                                                                              ##STR70##      7'                                         1 1  bond   CO  bond                                                                              ##STR71##      7'                                         1 1  bond   CO  bond                                                                              ##STR72##      7'                                         1 1  bond   CO  bond                                                                              ##STR73##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR74##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR75##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR76##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR77##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR78##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR79##      7'                                         1 zero                                                                             O      CO  bond                                                                              ##STR80##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR81##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR82##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR83##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR84##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR85##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR86##      7'                                         1 zero                                                                             S      CO  bond                                                                              ##STR87##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR88##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR89##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR90##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR91##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR92##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR93##      7'                                         1 zero                                                                             SO.sub.2                                                                             CO  bond                                                                              ##STR94##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR95##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR96##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR97##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR98##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR99##      7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR100##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      CO  bond                                                                              ##STR101##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR102##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR103##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR104##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR105##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR106##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR107##     7'                                         1 zero                                                                             CHCH   CO  bond                                                                              ##STR108##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR109##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR110##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR111##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR112##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR113##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR114##     7'                                         1 zero                                                                             OCNH   CO  bond                                                                              ##STR115##     7'                                         2 1  bond   CO  bond                                                                              ##STR116##     7'                                         2 1  bond   CO  bond                                                                              ##STR117##     7'                                         2 1  bond   CO  bond                                                                              ##STR118##     7'                                         2 1  bond   CO  bond                                                                              ##STR119##     7'                                         2 1  bond   CO  bond                                                                              ##STR120##     7'                                         2 1  bond   CO  bond                                                                              ##STR121##     7'                                         2 1  bond   CO  bond                                                                              ##STR122##     7'                                         1 1  bond   O   bond                                                                              ##STR123##     7'                                         1 1  bond   O   bond                                                                              ##STR124##     8'                                         1 1  bond   O   bond                                                                              ##STR125##     7'                                         1 1  bond   O   bond                                                                              ##STR126##     7'                                         1 1  bond   O   bond                                                                              ##STR127##     7'                                         1 1  bond   O   bond                                                                              ##STR128##     7'                                         1 1  bond   O   bond                                                                              ##STR129##     7'                                         1 1  bond   O   bond                                                                              ##STR130##     7'                                         1 1  bond   O   bond                                                                              ##STR131##     7'                                         1 1  bond   O   bond                                                                              ##STR132##     7'                                         1 1  bond   O   bond                                                                              ##STR133##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR134##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR135##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR136##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR137##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR138##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR139##     7'                                         1 zero                                                                             O      O   bond                                                                              ##STR140##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR141##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR142##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR143##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR144##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR145##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR146##     7'                                         1 zero                                                                             S      O   bond                                                                              ##STR147##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR148##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR149##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR150##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR151##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR152##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR153##     7'                                         1 zero                                                                             SO.sub.2                                                                             O   bond                                                                              ##STR154##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR155##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR156##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR157##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR158##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR159##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR160##     7'                                         1 zero                                                                             NCO.sub.2 allyl                                                                      O   bond                                                                              ##STR161##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR162##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR163##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR164##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR165##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR166##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR167##     7'                                         1 zero                                                                             CHCH   O   bond                                                                              ##STR168##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR169##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR170##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR171##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR172##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR173##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR174##     7'                                         1 zero                                                                             OCNH   O   bond                                                                              ##STR175##     7'                                         2 1  bond   O   bond                                                                              ##STR176##     7'                                         2 1  bond   O   bond                                                                              ##STR177##     7'                                         2 1  bond   O   bond                                                                              ##STR178##     7'                                         2 1  bond   O   bond                                                                              ##STR179##     7'                                         2 1  bond   O   bond                                                                              ##STR180##     7'                                         2 1  bond   O   bond                                                                              ##STR181##     7'                                         2 1  bond   O   bond                                                                              ##STR182##     7'                                         __________________________________________________________________________

EXAMPLE 7 Preparation of Carbapenem Derivative 7 ##STR183##

To a stirred solution of 24.6 mg(0.044 mmole) of salt 6 in 1.0 ml ofmethylene chloride at room temperature was added 6.9 mg(0.026 mmole ) oftriphenylphosphine, 10.1 mg(0.0088 mmole) oftetrakistriphenylphosphinepalladium(0), and 96.5 μL(0.048 mmole) of a0.5M solution of sodium-2-ethylhexanoate. The resulting mixture wasstirred under nitrogen for 0.5 hours.

The mixture was chilled in an ice-water bath and diethyl ether wasadded. The separated material was collected by centrifugation anddecantation of the supernatant. The crude product was washed analogouslywith ether and dried in vacuo to give 26.8 mg of residue.

Purification by reverse phase plate layer chromatography [onedevelopment H₂ O--CH₃ CN(7:3)] gave after extraction, concentration, andlyophilization 3.3 mg(16%) of product 7.

¹ H NMR[D₂ O--CD₃ CN(5:2)] δ: 1.5(d, 3H), 2.1-2.4(m, 2H), 3.28-3.6(m,3H), 3.8(m, 1H), 4.1(s, N--CH₃), 4.5-4.7(m, 2H), 4.8(s,HDO), 5.67(s,2H), 7.5-8.1(m, 9H), and 9.0(bs). UV(H₂ O): λ_(max) 303,265 nm.

EXAMPLE 7A Preparation of Carbapenems

Using the procedure of example 7, the following hexacyclic carbapenemsare prepared:

    __________________________________________________________________________     ##STR184##                                                                   m  n   X      Z   Z'  R.sup.a           Position R.sup.a                      __________________________________________________________________________    1  1   bond   CO  bond                                                                               ##STR185##       7'                                    1  1   bond   CO  bond                                                                               ##STR186##       8'                                    1  1   bond   CO  bond                                                                               ##STR187##       7'                                    1  1   bond   CO  bond                                                                               ##STR188##       7'                                    1  1   bond   CO  bond                                                                               ##STR189##       7'                                    1  1   bond   CO  bond                                                                               ##STR190##       7'                                    1  1   bond   CO  bond                                                                               ##STR191##       7'                                    1  1   bond   CO  bond                                                                               ##STR192##       7'                                    1  1   bond   CO  bond                                                                               ##STR193##       7'                                    1  1   bond   CO  bond                                                                               ##STR194##       7'                                    1  1   bond   CO  bond                                                                               ##STR195##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR196##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR197##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR198##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR199##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR200##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR201##       7'                                    1  zero                                                                              O      CO  bond                                                                               ##STR202##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR203##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR204##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR205##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR206##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR207##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR208##       7'                                    1  zero                                                                              S      CO  bond                                                                               ##STR209##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR210##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR211##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR212##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR213##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR214##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR215##       7'                                    1  zero                                                                              SO.sub.2                                                                             CO  bond                                                                               ##STR216##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR217##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR218##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR219##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR220##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR221##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR222##       7'                                    1  zero                                                                              NH     CO  bond                                                                               ##STR223##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR224##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR225##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR226##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR227##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR228##       7'                                    1  zero                                                                              CH CH  CO  bond                                                                               ##STR229##       7'                                    1  zero                                                                              CHCH   CO  bond                                                                               ##STR230##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR231##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR232##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR233##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR234##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR235##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR236##       7'                                    1  zero                                                                              OCNH   CO  bond                                                                               ##STR237##       7'                                    2  1   bond   CO  bond                                                                               ##STR238##       7'                                    2  1   bond   CO  bond                                                                               ##STR239##       7'                                    2  1   bond   CO  bond                                                                               ##STR240##       7'                                    2  1   bond   CO  bond                                                                               ##STR241##       7'                                    2  1   bond   CO  bond                                                                               ##STR242##       7'                                    2  1   bond   CO  bond                                                                               ##STR243##       7'                                    2  1   bond   CO  bond                                                                               ##STR244##       7'                                    1  1   bond   O   bond                                                                               ##STR245##       7'                                    1  1   bond   O   bond                                                                               ##STR246##       8'                                    1  1   bond   O   bond                                                                               ##STR247##       7'                                    1  1   bond   O   bond                                                                               ##STR248##       7'                                    1  1   bond   O   bond                                                                               ##STR249##       7'                                    1  1   bond   O   bond                                                                               ##STR250##       7'                                    1  1   bond   O   bond                                                                               ##STR251##       7'                                    1  1   bond   O   bond                                                                               ##STR252##       7'                                    1  1   bond   O   bond                                                                               ##STR253##       7'                                    1  1   bond   O   bond                                                                               ##STR254##       7'                                    1  1   bond   O   bond                                                                               ##STR255##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR256##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR257##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR258##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR259##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR260##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR261##       7'                                    1  zero                                                                              O      O   bond                                                                               ##STR262##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR263##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR264##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR265##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR266##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR267##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR268##       7'                                    1  zero                                                                              S      O   bond                                                                               ##STR269##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR270##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR271##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR272##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR273##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR274##       7'                                    1  zero                                                                              SO.sub.2                                                                             O   bond                                                                               ##STR275##       7'                                    1  zero                                                                              SO.sub. 2                                                                            O   bond                                                                               ##STR276##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR277##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR278##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR279##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR280##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR281##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR282##       7'                                    1  zero                                                                              NH     O   bond                                                                               ##STR283##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR284##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR285##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR286##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR287##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR288##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR289##       7'                                    1  zero                                                                              CHCH   O   bond                                                                               ##STR290##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR291##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR292##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR293##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR294##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR295##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR296##       7'                                    1  zero                                                                              C(O)NH O   bond                                                                               ##STR297##       7'                                    2  1   bond   O   bond                                                                               ##STR298##       7'                                    2  1   bond   O   bond                                                                               ##STR299##       7'                                    2  1   bond   O   bond                                                                               ##STR300##       7'                                    2  1   bond   O   bond                                                                               ##STR301##       7'                                    2  1   bond   O   bond                                                                               ##STR302##       7'                                    2  1   bond   O   bond                                                                               ##STR303##       7'                                    2  1   bond   O   bond                                                                               ##STR304##       7'                                    __________________________________________________________________________

What is claimed is:
 1. A compound represented by formula I: ##STR305##wherein: m is an integer 0, 1, 2, 3, 4 or 5;n is an integer 0, 1, 2, 3or 4; X represents a member selected from the group consisting of: (a) abond; (b) --O--; (c) --S(O)_(x) -- with x equal to 0, 1 or 2; (d)--C(O)--; (e) --NR'--; (f) --CH═CH--; (g) --C(O)NR'--; (h) --NR'C(O)--;(i) --CO₂ --; (j) --OC(O)--; (k) --SO₂ NR'-- and (l) --NR'SO₂ -- with R'representing H, C₁ to C₄ alkyl or acetyl;the values of m, n and X beingselected such that ring B constitutes a 6 to 10 membered ring; Yrepresents a member selected from the group consisting of: H, a negativecharge, a pharmaceutically acceptable ester, a carboxylate protectinggroup and a metal cation; R¹ and R² independently represent H, CH₃ --,CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂CH(OH)--, F₂ CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ -- or (CH₃)₂CF--; one of Z and Z' represents a bond and the other represents amember selected from the group consisting of: --CH═CH--, --C(O)NR^(f)--, --NR^(f) C(O)--, --S(O)_(x) NR^(f) --, --NR^(f) S(O)_(x) --,--C(O)--, --OC(O)--, --C(O)O--, --O--, --S(O)_(x) -- with x equal to 0,1 or 2, or --NR^(f) -- with R^(f) representing H, C₁ to C₄ alkyl,--C(O)--C1-4 alkyl, --C(O)--C1-4 alkyl substituted with R^(q), such thatring C is a 5 or 6 membered ring; one of the R^(a) groups represents Hor W as defined below, and the other represents one of the groups (a)through (d): ##STR306## when one of the R^(a) groups represents##STR307## A represents --(CR³ R⁴)_(r) --Q--(CR³ R⁴)_(s) -- wherein r is0-6, s is 1-6 and Q represents: a covalent bond, --O--, --S(O)_(x) --with x equal to 0, 1 or 2, --NR³ --, --SO₂ NR³ --, --NR³ SO₂ --,--C(O)NR³ --, --NR³ C(O)--, --CR³ ═CR⁴ --, --C(O)-- or --OC(O)--; withR³ and R⁴ independently representing H or C₁₋₄ lower alkyl, and (CR³R⁴)_(s) -- being attached to the ring nitrogen; ##STR308## represents a5- or 6-membered monocyclic heterocycle or an 8-10 membered bicyclicheterocycle, bonded to A through the ring nitrogen and having asubstituent group R^(d) optionally attached to the ring nitrogen, andhaving 0-3 R^(c) groups attached to other atoms of the heterocyclicgroup, said ring nitrogen being tertiary or quaternary by virtue of A,the ring bonds and R^(d) which may be optionally attached, saidheterocyclic group being aromatic, partially aromatic or non-aromatic,said heterocycle also containing 0-3 additional nitrogen atoms and 0-1oxygen or sulfur atom; each R^(c) independently represents W as definedbelow or NR^(y) R^(z), wherein R^(y) and R^(z) independently representH, C₁ to C₄ alkyl, C₁ to C₄ alkyl substituted with R^(q), or R^(y) andR^(z) are taken together to represent either a 3- to 5-memberedalkylidene radical to form a ring, optionally substituted with R^(q), ora 2- to 4-membered alkylidene radical interrupted by O or S(O)_(x) withx equal to 0, 1 or 2, to form a ring, said alkylidene being optionallysubstituted with R^(q) ; R^(q) is selected from the group consisting of:hydroxy, methoxy, cyano, --C(O)NH₂, --OC(O)NH₂, --CHO, --OC(O)N(CH₃)₂,--SO₂ NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃, --F, --CF₃, --SO₃ M^(b)with M^(b) representing H or alkali metal, or --CO₂ M^(a), where M^(a)is H, alkali metal, methyl or phenyl; tetrazolyl, where the point ofattachment is the carbon atom of the tetrazole ring and one of thenitrogen atoms is mono-substituted by M^(a) as defined above; each R^(d)independently represents hydrogen, NH₂, O-- or C₁ to C₄ alkyl,optionally monosubstituted with R^(q) as defined above; when one R^(a)group represents ##STR309## A' represents --(CR³ R⁴)_(m) '--Q--(CR³R⁴)m'-- with each m' independently equal to 0-6, and Q, R³ and R⁴ asdefined above, except that when each m' is 0, Q is not a covalent bond,and --(CR³ R⁴)m' attached to the phenyl ring; ##STR310## represents a 5-or 6-membered monocyclic heterocycle or an 8-10 membered bicyclicheterocycle, said heterocycle being aromatic, partially aromatic ornon-aromatic, bonded to A' through an atom other than the ring nitrogen,and optionally having 0-2 R^(d) substituent groups attached to the ringnitrogen, said nitrogen in the heterocycle being tertiary or quaternaryby virtue of the ring bonds and the optional R^(d) groups which may beattached; said heterocycle may further contain 0-1 oxygen or sulfur atomand 0-2 additional nitrogen atoms therein; R^(c) and R^(d) are asdefined above; when one R^(a) group represents (c) --Ap--NR¹⁰ R¹¹R¹²(0-1) ; A is as defined above and p is an integer 0 or 1; R¹⁰, R¹¹and where present, R¹², are independently H, C₁₋₄ alkyl or C₁₋₄ alkylmonosubstituted with R^(q) ; or R¹⁰, R¹¹ and R¹² may be taken incombination to represent a C₄ to C₁₀ alkanetriyl group, optionallysubstituted with up to three W groups, with W as defined below; when oneR^(a) group represents (d), A', p, the N containing ring, R^(c) andR^(d) are as previously defined; each W independently represents amember selected from the group consisting of:a) --CF₃ ; b) a halogenatom selected from the group consisting of: --Br, --Cl, --F, and --I; c)--OC₁₋₄ alkyl, wherein the alkyl is optionally mono-substituted byR^(q), where R^(q) is as defined above; d) --OH; e) --OC(O)R^(s), whereR^(s) is C₁₋₄ alkyl or phenyl, each of which is optionallymono-substituted by R^(q) as defined above; f) --OC(O)N(R^(y))R^(z),where R^(y) and R^(z) are independently H, C₁₋₄ alkyl, (optionallymono-substituted by R^(q) as defined above, or are taken together torepresent a 3- to 5-membered alkylidene radical which forms a ring whichmay be optionally substituted with R^(q) as defined above, or a 2- to4-membered alkylidene radical interrupted by --O--, --S--, --S(O)-- orS(O)₂ -- which forms a ring, said ring being optionally mono-substitutedwith R^(q) as defined above; g) --S(O)_(n) --R^(s), where n=O-2, andR^(s) is defined above; h) --SO₂ N(R^(y))R^(z), where R^(y) and R^(z)are as defined above; i) N₃ j) --N(R^(t))C(O)H, where R^(t) is H or C₁₋₄alkyl, said alkyl group being optionally mono-substituted with R^(q) asdefined above; k) --N(R^(t))C(O)C₁₋₄ alkyl, wherein R^(t) is as definedabove; l) --N(R^(t))C(O)OC₁₋₄ alkyl, where R^(t) is as defined above; m)--N(R^(t))C(O)N(R^(y))R^(z) where R^(t), R^(y) and R^(z) are definedabove; n) --N(R^(t))SO₂ R^(s), where R^(s) and R^(t) are as definedabove; o) --CN; p) a formyl or acetalized formyl radical selected fromthe group consisting of: --C(O)H and --CH(OCH₃)₂ ; q) --C(OCH₃)₂ C₁ -C₄alkyl, where the alkyl is optionally mono-substituted by R^(q) asdefined above; r) --C(O)R^(s), where R^(s) is as defined above; s)--(C═NOR^(z))R^(y) where R^(y) and R^(z) are as defined above, exceptthey may not be joined together to form a ring; t) --C(O)OC₁₋₄ alkyl,where the alkyl is optionally mono-substituted by R^(q) as definedabove; u) --C(O)N(R^(y))R^(z), where R^(y) and R^(z) are as definedabove; v) --C(O)N(OR^(y))R^(z), where R^(y) and R^(z) are as definedabove, except they may not be joined together to form a ring; w)--C(S)N(R^(y))R^(z) where R^(y) and R^(z) are as defined above; x)--COOM^(a) where M^(a) is as defined above; y) --SCN; z) --SCF₃ ; aa)tetrazolyl, where the point of attachment is the carbon atom of thetetrazole ring and one of the nitrogen atoms is mono-substituted byhydrogen, an alkali metal or a C₁ -C₄ alkyl optionally substituted byR^(q) as defined above; ab) an anionic function selected from the groupconsisting of:phosphono which is P═O(OM^(a))₂ ; alkylphosphono which isP═O(OM^(a))(OC₁₋₄ alkyl); alkylphosphinyl which is P═O(OM^(a))(C₁₋₄alkyl); phosphoramido which is selected from the group consisting ofP═O(OM^(a))NR^(y) R^(z) and P═O(OM^(a))NHR^(x) ; sufino which is SO₂M^(a) ; and sulfo which is SO₃ M^(a) ; acylsulfonamides selected fromthe group consisting of: SO₂ NM^(a) CON(R^(y))R^(z) ; and SO₂ NM^(a) CN,where R^(x) is phenyl or heteroaryl, where heteroaryl is a monocyclicaromatic hydrocarbon group having 5 or 6 ring atoms, in which a carbonatom is the point of attachment, in which one of the carbon atoms hasbeen replaced by a nitrogen atom, in which one additional carbon atom isoptionally replaced by a heteroatom selected from O or S, and in whichfrom 1 to 2 additional carbon atoms are optionally replaced by anitrogen heteroatom, and where the phenyl and heteroaryl are optionallymono-substituted by R^(q), said R^(q), M^(a), R^(y) and R^(z) being asdefined above; ac) a C₅ -C₇ cycloalkyl group in which one of the carbonatoms in the ring is replaced by a heteroatom selected from O, S, NH, orN (C₁ -C₄ alkyl) and in which one additional carbon may be replaced bythe NH or N(C₁ -C₄ alkyl), and in which at least one carbon atomadjacent to each nitrogen heteroatom has both of its attached hydrogenatoms replaced by one oxygen thus forming a carbonyl moiety and thereare one or two carbonyl moieties present in the ring; ad) a C₂ -C₄alkenyl radical, optionally monosubstituted by one of the substituentsa) to ac) above and phenyl which is optionally substituted by R^(q) asdefined above; ae) a C₂ -C₄ alkynyl radical, optionally monosubstitutedby one of the substituents a) to ac) above; af) a C₁ -C₄ alkyl radical;ag) a C₁ -C₄ alkyl group mono-substituted by one of the substituents a)-ac) above; ah) a 2-oxazolidinonyl moiety in which the point ofattachment is the nitrogen atom of the oxazolidinone ring, the ringoxygen atom is optionally replaced by a heteroatom selected from S andNR^(t) (where R^(t) is as defined above) and one of the saturated carbonatoms of the oxazolidinone ring is optionally mono-substituted by one ofthe substituents a) to ag) above or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1, wherein R¹ is hydrogen and R² is(R)CH₃ CH(OH)-- or (R)CH₃ CH(F)--.
 3. A compound according to claim 1 inwhich Z represents a carbonyl --C(O)-- and R^(a) at position 7'represents one of groups (a) through (d).
 4. A compound according toclaim 1 wherein Z represents --O-- and R^(a) is attached to position 7'.5. The compound of claim 1, wherein Z represents a member selected fromthe group consisting of: --CH═CH--, --C(O)--, --O-- and --S(O)_(x) withx equal to 0, 1 or 2, and the group --(CH₂)_(m) --X--(CH₂)_(n) --represents a member selected from the group consisting of: --CH₂ --O--;--CH₂ CH₂ --; --CH₂ NH--; --CH₂ SO₂ --; --CH₂ C(O)-- and --CH₂ OC(O)--.6. The compound of claim 1, wherein one R^(a) represents group (a) or(b), and the other R^(a) represents a member selected from the groupconsisting of:H; --CF₃ ; --Br; --I; --Cl; --F; --OC₁₋₄ alkyl; --OC₁₋₄alkyl substituted with 1-3 R^(q) groups, which are independentlyselected from --OH, --OCH₃, --CN, --F, --CF₃, and --COOM^(a), whereM^(a) is H, alkali metal or methyl; --OH; --S(O)_(x) R^(s) with x=0 or 2and R^(s) =C₁₋₄ alkyl or phenyl, each of which is optionallymonosubstituted with R^(q), wherein R^(q) is selected from the groupconsisting of: hydroxy, methoxy, cyano, --C(O)NH₂, --OC(O)NH₂, --CHO,--OC(O)N(CH₃)₂, --SO₂ NH₂, --SO₂ N(CH₃)₂, --SOCH₃, --SO₂ CH₃ --F, --CF₃,--SO₃ M^(b) with M^(b) representing H or alkali metal, or --CO₂ M^(a),where M^(a) is H, alkali metal, methyl or phenyl; tetrazolyl, where thepoint of attachment is the carbon atom of the tetrazole ring and one ofthe nitrogen atoms is mono-substituted by M^(a) as defined above.
 7. Thecompound of claim 1, containing one R^(a) group selected form (a), (b)and (d), said R^(a) group being substituted with from 0-3 groups R^(c)or R^(a), said R^(c) groups being attached to ring carbon and said R^(d)groups being attached to ring nitrogen atoms,wherein the R^(c)substituents attached to ring carbon atoms are selected from the groupconsisting of --NH₂, --SCH₃, --SOCH₃, --CH₂ OH, --(CH₂)₂ OH, --OCH₃,--COOM^(b), --CH₂ COOM^(b), --CH₂ CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂ SCH₃,--SO₃ M^(b), --CH₂ SO₃ M^(b), --CH₂ CH₂ SO₃ M^(b), --Br, --Cl, --F, --I,--CH₃, --CH₂ CH₃, --CH₂ CONH₂ and CH₂ CON(C₁ -C₄ alkyl)₂ and the R^(d)substituents attached to ring nitrogen atoms are selected from the groupconsisting of --CH₂ OH, --(CH₂)₂ OH, --CH₂ COOM^(b), --CH₂ SOCH₃, --CH₂SCH₃, --CH₂ SO₃ M^(b), --CH₂ CH₂ SO₃ M^(b), --CH₃, --CH₂ CH₃, --CH₂CONH₂ and --CH₂ CON(C₁ -C₄ alkyl)₂.
 8. The compound of claim 2 whereinthe R^(d) substituents attached to the nitrogen atom are selected fromthe group consisting of: hydrogen, --CH₃, --CH₂ CH₃, --CH₂ CH₂ CH₃,--CH₂ COOM^(b), CH₂ C(O)NH₂, --CH₂ SO₂ NH₂, --CH₂ SO₃ M^(b), --NH₂ and--O--.
 9. The compound of claim 2, wherein the spacer moiety, A, isselected from the group consisting of: --CH₂ --, --CH₂ CH₂ --, --CH₂ CH₂CH₂ --, --CH₂ CH₂ CH₂ CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --, --SO₂ CH₂ --,--SCH₂ CH₂ --, --SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂ CH₂ --,--N(CH₃) CH₂ CH₂ --, --CH₂ N(CH₃)CH₂ CH₂ --, --SO₂ NHCH₂ CH₂ --, --COCH₂--, --CH═CHCH₂ -- and --CH₂ --O--CH₂ CH₂ --.
 10. The compound of claim2, wherein the spacer moiety, A', is selected from the group consistingof: --O--, --S--, --NH--, --SO₂ --, --SO₂ NH--, --CONH--, --CH═CH--,--CH₂ S--, --CH₂ NH--, CONHCH₂ --, --SO₂ NH CH₂ --, --CH₂ --, --CH₂ CH₂--, --CH₂ CH₂ CH₂ --, CH₂ CH₂ CH₂ CH₂ --, --OCH₂ CH₂ --, --SOCH₂ --,--SO₂ CH₂ --, --SCH₂ CH₂ --, --SOCH₂ CH₂ --, --SO₂ CH₂ CH₂ --, --NHCH₂CH₂ --, --N(CH₃)CH₂ CH₂ --, --CH₂ N(CH₃)CH₂ CH₂ --, --SO₂ NHCH₂ CH₂ --,--CO CH₂ --, --CH═CHCH₂ -- and --CH₂ --O--CH₂ CH₂ --.
 11. The compoundof claim 2, wherein one of the R^(a) groups represents one of (a)through (d) and the other R^(a) groups are independently selected fromthe group consisting of:

    ______________________________________                                        --OCH.sub.3                                                                   --OCH.sub.2 CH.sub.2 OH                                                                         --OCH.sub.2 CO.sub.2 Me                                     --F               --CF.sub.3                                                  --Br              --Cl                                                        --OH              --I                                                         --OCONH.sub.2     --OCOCH.sub.3                                               --SOCH.sub.3      --SCH.sub.3                                                 --SCH.sub.2 CH.sub.2 OH                                                                         --SO.sub.2 CH.sub.3                                         --SO.sub.2 NH.sub.2                                                                             --SOCH.sub.2 CH.sub.2 OH                                    --NHCHO           --SO.sub.2 N(CH.sub.3).sub.2                                --NHCO.sub.2 CH.sub.3                                                                           --NHCOCH.sub.3                                              --CN              --NHSO.sub.2 CH.sub.3                                       --COCH.sub.3      --CHO                                                       --CH═NOH      --COCH.sub.2 OH                                             --CH═NOCH.sub.2 CO.sub.2 Me                                                                 --CH═NOCH.sub.3                                         --SO.sub.2 CH.sub.2 CH.sub.2 OH                                                                 --CH═NOCMe.sub.2 CO.sub.2 Me                            --CH═NOCMe.sub.2 CO.sub.2 Me                                                                --CO.sub.2 CH.sub.2 CH.sub.2 OH                             --CONH.sub.2      --CONHCH.sub.3                                              --CON(CH.sub.3).sub.2                                                                           --CONHCH.sub.2 CN                                           --CONHCH.sub.2 CONH.sub.2                                                                       --CONHCH.sub.2 CO.sub.2 Me                                  --CONHOH          --CONHCH.sub.3                                              tetrazolyl        --CO.sub.2 Me                                               -- SCF.sub.3      --PO.sub.3 HMe                                              --CONHSO.sub.2 Ph --CONHSO.sub.2 NH.sub.2                                     --SO.sub.3 Me     --SO.sub.2 NHCN                                             --SO.sub.2 NHCONH.sub.2                                                                         --CH═CHCN                                               --CH═CHCONH.sub.2                                                                           --CH═CHCO.sub.2 Me                                      --Cbn,4 C--CONH.sub.2                                                                           --Cbn,4 C--CN                                               --CH.sub.2 OH     --CH.sub.2 N.sub.3                                          --CH.sub.2 CO.sub.2 Me and                                                                      --CH.sub.2 I.sub..                                          ______________________________________                                    


12. A compound according to claim 4, wherein Y is Na⁺, K⁺ or a negativecharge.
 13. A compound in accordance with claim 1 wherein:R^(a) isselected from the group consisting of ##STR311## wherein A and A' areindependently selected from the group consisting of --CH₂ --, --CH₂ CH₂-- and --CH₂ CH₂ CH₂ --; ##STR312## represents a member selected fromthe group consisting of ##STR313## represents a member selected from thegroup consisting of ##STR314##
 14. A compound of claim 2, wherein oneR^(a) substituent is selected from the group consisting of: ##STR315##in which W' is selected from the group consisting of S, SO and SO₂, andwhere A' and R^(c) are shown to have an indefinite position, they may beattached to any carbon atom of the ring.
 15. The compound of claim 1,wherein one R^(a) group represents one member selected from the groupconsisting of: ##STR316## and where R^(d) or A' is shown to have anindefinite position, they may be attached to any carbon atom of thering.
 16. A compound in accordance with claim 1 wherein Y represents apharmaceutically acceptable ester forming group.
 17. A compound inaccordance with claim 16 wherein the pharmaceutically acceptable esterforming group is a biolabile ester forming group.
 18. A compoundrepresented by the formula: ##STR317## wherein: m and n represent 1; mrepresents 1 and n represents zero; or m represents 2 and n representszero;X is selected from the group consisting of: a bond, --O--, --S--,--SO₂ --, --C(O)--, --NH--, --CH═CH-- and --C(O)NH--; Z and Z' represent--C(O)-- and a bond, respectively; --S-- and a bond, respectively; --SO₂-- and a bond, respectively; --O-- and a bond, respectively; --NH-- anda bond, respectively; or --OC(O) and a bond, respectively; Y representsa negative charge, and R^(a) is selected from the group consisting of:##STR318##
 19. A compound of claim 2, wherein one R^(a) substituent isselected from the group consisting of: ##STR319## in which W' representsNR' with R' representing H, C₁₋₄ alkyl or acetyl; and where A' and R^(c)are shown to have an indefinite position, they may be attached to anycarbon atom of the ring.
 20. A pharmaceutical composition for comprisinga compound of claim 1 and a pharmaceutically acceptable carrier.
 21. Apharmaceutical composition comprising a compound of claim 1 and a DHPinhibitor in combination with a pharmaceutically acceptable carrier. 22.A pharmaceutical composition according to claim 21 wherein the DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.
 23. A method of treating a bacterial infection in a mammal in needof such treatment comprising administering to said mammal a compound ofclaim 1 in an amount effective to treat said bacterial infection.
 24. Amethod of treating a bacterial infection in a mammalian subject in needof such treatment, comprising administering to such subject anantibacterially effective amount of a compound of claim 1 and aninhibitorily effective amount of a DHP inhibitor.
 25. The methodaccording to claim 24, wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethyl-thio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.